Diazepan derivatives

ABSTRACT

The invention is concerned with novel diazepan derivatives of formula (I) 
                         
wherein A, X, R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , m and n are as defined in the description and in the claims, as well as physiologically acceptable salts thereof. These compounds are antagonists of CCR-2 receptor, CCR-5 receptor and/or CCR-3 receptor and can be used as medicaments.

PRIORITY TO RELATED APPLICATIONS

This application claims the benefit of European Application No. 06112832.8, filed Apr. 20, 2006, which is hereby incorporated by reference in its entirety.

BACKGROUND

Proinflammatory chemokines are considered to be involved in the development of atherosclerosis and other important diseases with inflammatory components like rheumatoid arthritis, asthma, multiple sclerosis, transplant rejection and ischemia reperfusion injury with specific prominent effects in nephropathy and peripheral vascular diseases. Monocyte Chemotactic protein 1 is considered to be the major stimulated chemokine mediating inflammatory processes in these diseases through the CCR2 receptor on monocytes and on some T lymphocytes. In addition MCP-1/CCR2 are in discussion to be related to the progression of the metabolic syndrome to more severe stages of obese and diabetic diseases.

CCR2 has also been linked to HIV infection, and consequently the course of autoimmune diseases, through its heterodimerization with CCR5 which has a role as coreceptor for viral entry into host cells.

Thus, CCR2 can be a target of a new medicine for treatment of peripheral vascular diseases, and more specifically for treatment of patients with critical limb ischemia. Furthermore, study results and experiences from the development of a new CCR2 medicine for this indication may facilitate a follow-up development for treatment of atherosclerosis. There is a large body of information from animal models of MCP-1 and CCR2 ko mice in wt or apoE−/− or LDL-R−/− backgrounds showing that the MCP-1/CCR2 pathway is essential for monocyte/macrophage recruitment, and also for intimal hyperplasia and the formation and stability of atherosclerotic lesions. In addition, numerous reports describe involvement of the MCP-1/CCR2 pathway in man post injury and in various inflammatory processes, including such in vascular beds.

SUMMARY OF THE INVENTION

The invention is concerned with novel diazepan derivatives of formula (I),

wherein

-   -   A is aryl or heteroaryl, said aryl and said heteroaryl being         optionally substituted by one to three substituents         independently selected from the group consisting of halogen,         benzyloxy, heteroaryl-C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkoxy and         halo C₁₋₆ alkoxy, or said aryl and said heteroaryl being         optionally substituted by C₁₋₆ alkylenedioxy;     -   X is —N(R¹)(R²) or —N⁺(R¹)(R²)(R⁷);         R¹ and R² are, independently to each other, hydrogen, C₁₋₆         alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, hydroxy C₂₋₆ alkyl, C₁₋₆         alkoxy C₂₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆ alkyl,         C₇₋₁₀ bicycloalkyl, phenyl C₁₋₃ alkyl, heteroaryl C₁₋₃ alkyl,         heterocyclyl or heterocyclyl C₁₋₆ alkyl, in which the cycloalkyl         of said C₃₋₇ cycloalkyl and said C₃₋₇ cycloalkyl C₁₋₆ alkyl, the         phenyl of said phenyl C₁₋₃ alkyl, the heteroaryl of said         heteroaryl C₁₋₃ alkyl and the heterocyclyl of said heterocyclyl         and said heterocyclyl C₁₋₆ alkyl are optionally substituted by         one to three substituents independently selected from the group         consisting of R^(d); or     -   R¹ and R², together with the nitrogen atom to which they are         attached, form heterocyclyl optionally substituted by one to         three substituents independently selected from the group         consisting of R^(d), and one of the ring carbon atoms of said         heterocyclyl formed by R¹ and R² being optionally replaced with         a carbonyl group; and/or     -   one of the ring carbon atoms of the heterocyclyl formed by R¹         and R² may be a ring carbon atom of another ring which is C₃₋₇         cycloalkyl or heterocyclyl, one or two ring carbon atoms of said         another ring being optionally replaced by a carbonyl group, and         said another ring being optionally substituted by C₁₋₆ alkyl;     -   R³ and R⁴ are, independently to each other, hydrogen, hydroxy,         C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆         alkyl, C₁₋₆ alkoxycarbonyl, carboxyl, hydroxy-C₁₋₆ alkyl, C₁₋₆         alkoxy-C₁₋₆ alkyl, halogen or halo C₁₋₆ alkyl; or     -   R³ and R⁴, together with the carbon atom to which they are         attached, form C₃₋₇ cycloalkyl or heterocyclyl optionally         substituted by one to three substituents independently selected         from the group consisting of C₁₋₄ alkyl, halo C₁₋₄ alkyl and         halogen; or         R¹ is hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, hydroxy         C₁₋₆ alkyl, C₁₋₆ alkoxy C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇         cycloalkyl C₁₋₆ alkyl, C₇₋₁₀ bicycloalkyl, phenyl C₁₋₃ alkyl,         heteroaryl C₁₋₃ alkyl, heterocyclyl or heterocyclyl C₁₋₆ alkyl,         in which the cycloalkyl of said C₃₋₇ cycloalkyl and said C₃₋₇         cycloalkyl C₁₋₆ alkyl, the phenyl of said phenyl C₁₋₃ alkyl, the         heteroaryl of said heteroaryl C₁₋₃ alkyl and the heterocyclyl of         said heterocyclyl and said heterocyclyl C₁₋₆ alkyl are         optionally substituted by one to three substituents         independently selected from the group consisting of R^(d);     -   R³ is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl         C₁₋₆ alkyl, halogen or halo C₁₋₆ alkyl;     -   R² and R⁴, together with the nitrogen atom to which R² is         attached, the carbon atom to which R⁴is attached and the C₁₋₂         alkylene between said nitrogen atom and said carbon atom, if         any, form heterocyclyl optionally substituted by one to three         substituents independently selected from the group consisting of         C₁₋₆ alkyl and fluorine;     -   R⁵ and R⁶ are, independently to each other, hydrogen, fluoro,         C₁₋₆ alkyl or C₃₋₇ cycloalkyl;     -   R⁷ is C₁₋₆ alkyl;     -   R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are, independently to each other,         hydrogen, C₁₋₆ alkyl or C₃₋₇ cycloalkyl;     -   R^(d) is hydroxy, cyano, NR^(a)R^(b), halogen, C₁₋₆ alkyl, halo         C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy C₁₋₆         alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkoxycarbonyl, acyl,         —C(O)NR^(a)R^(b), —NR^(a)—C(O)—R^(b), —NR^(a)—C(O)—OR^(b),         —NR^(a)—C(O)—NR^(b), —NR^(a)—SO₂—R^(b), —NR^(a)—SO₂—NR^(b)R^(c),         —OC(O)NR^(a)R^(b), —OC(O)OR^(a), C₁₋₆ alkylsulfonyl, C₁₋₆         alkylsulfinyl, C₁₋₆ alkylthio, phenyl, phenyl C₁₋₃ alkyl,         heteroaryl, heteroaryl C₁₋₃ alkyl and heterocyclyl, and the         phenyl of said phenyl and said phenyl C₁₋₃ alkyl, the heteroaryl         of said heteroaryl and said heteroaryl C₁₋₃ alkyl, and the         heterocyclyl being optionally substituted by one to three         substituents independently selected from the group consisting of         hydroxy, cyano, NR^(a)R^(b), halogen, C₁₋₆ alkyl, halo C₁₋₆         alkyl, hydroxy C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, acyl,         —C(O)NR^(a)R^(b), —NR^(a)—C(O)—R^(b), —NR^(a)—C(O)—OR^(b),         —NR^(a)—C(O)—NR^(b), —NR^(a)—SO₂—R^(b), —NR^(a)—SO₂—NR^(b)R^(c),         —OC(O)NR^(a)R^(b), —OC(O)OR^(a), C₁₋₆ alkylsulfonyl, C₁₋₆         alkylsulfinyl and C₁₋₆ alkylthio, and one or two ring carbon         atoms of the heterocyclyl being optionally replaced with a         carbonyl group;     -   R^(a), R^(b) and R^(c) are independently hydrogen or C₁₋₆ alkyl;     -   n is an integer of 0 to 3;     -   m is an integer of 0 to 3;     -   m+n is an integer of 1 to 5;         or prodrugs or pharmaceutically acceptable salts thereof.

Further, the invention is concerned with a process and an intermediate for the manufacture of the above compounds, pharmaceutical preparations which contain such compounds, the use of these compounds for the production of pharmaceutical preparations.

The compounds of formula (I) are CCR2 receptor (Chemokine Receptor 2/Monocyte chemotactic protein 1 receptor) antagonists and also CCR-5 receptor (Chemokine Receptor 5) and/or CCR-3 receptor (Chemokine Receptor 3) antagonists. Chemokines are a family of small, secreted proinflammatory cytokines functioning as chemoattractants for leukocytes. They promote trafficking of leukocytes from vascular beds into surrounding tissues in response to inflammatory signals. Chemotaxis starts upon chemokine binding to receptors (GPCRs) by initiating signaling pathways involving increased Ca-flux, inhibition of cAMP production, rearrangements of the cytoskeleton, activation of integrins and of cell motility processes and an increase in the expression of adhesion proteins.

DETAILED DESCRIPTION

The present invention provides the novel compounds of formula (I) which are CCR2 receptor antagonists, with some antagonist activity also at CCR-3 and CCR-5.

Definitions

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.

The term “halogen” or “halo” means fluorine, chlorine, bromine and iodine, with chlorine and fluorine being preferred.

The term “C₁₋₆ alkyl”, alone or in combination with other groups, means a branched or straight-chain monovalent alkyl radical, having one to six carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl. C₁₋₄ alkyl or C₁₋₃ alkyl is more preferred. The term “C₂₋₆ alkyl” means the same as “C₁₋₆ alkyl”, except that C₂₋₆ alkyl has two to six carbon atoms.

The term “hydroxy C₁₋₆ alkyl” means C₁₋₆ alkyl substituted by one or more, preferably one hydroxy group(s).

The term “halo C₁₋₆ alkyl” means C₁₋₆ alkyl substituted by one or more same or different halogen atoms.

The term “C₁₋₂ alkylene” means a linear saturated divalent hydrocarbon radical of one to two carbon atoms, such as methylene, ethylene.

The term “C₃₋₇ cycloalkyl”, alone or in combination with other groups, means a saturated monovalent mono-cyclic hydrocarbon radical of three to seven ring carbons, e.g., cyclopropyl, cyclobutyl, cyclohexyl.

The term “C₇₋₁₀ bicycloalkyl”, alone or in combination with other groups, means a saturated monovalent cyclic hydrocarbon radical of seven to ten ring carbons, having two rings, in which two or more ring carbon atoms of one ring are ring carbon atoms of the other ring, e.g., bicyclo[2.2.1]heptyl.

The term “C₁₋₆ alkoxy”, alone or in combination with other groups, means the group R′—O—, wherein R′ is a C₁₋₆ alkyl.

The term “halo C₁₋₆ alkoxy”, alone or in combination with other groups, means C₁₋₆ alkoxy substituted by one or more, preferably one to three halogens.

The term “C₁₋₆ alkylenedioxy” means —O—C₁₋₆ alkyl-O—. Methylenedioxy or 1,2-ethylenedioxy are preferred.

The term “C₃₋₆ alkenyl”, alone or in combination with other groups, means a straight-chain or branched hydrocarbon residue comprising a carbon-carbon double bond, having three to six carbon atoms, provided that the carbon atom of the attachment point of the C₃₋₆ alkenyl to the rest of the molecule is not bonded to another carbon atom of the C₃₋₆ alkenyl by a carbon-carbon double bond. An example of C₃₋₆ alkenyl is 2-propenyl.

The term “C₃₋₆-alkynyl”, alone or in combination with other groups, means a straight-chain or branched hydrocarbon residue comprising a carbon-carbon triple bond, having three to six carbon atoms, provided that the carbon atom of the attachment point of the C₃₋₆ alkynyl to the rest of the molecule is not bonded to another carbon atom of the C₃₋₆ alkynyl by a carbon-carbon triple bond. An example of C₃₋₆ alkynyl is 2-propynyl.

The term “acyl” means R—C(O)—, in which R is C₁₋₆ alkyl, halo C₁₋₆ alkyl, C₃₋₇ cycloalkyl or C₃₋₇ cycloalkyl C₁₋₆ alkyl.

The term “heterocyclyl”, alone or combination with other groups, means non-aromatic mono- or bi-cyclic radicals of four to nine ring atoms in which one to three ring atoms are heteroatoms independently selected from N, O and S(O)_(n) (where n is an integer from 0 to 2), the remaining ring atoms being C.

The term “aryl”, alone or combination with other groups, means phenyl or naphthyl.

The term “heteroaryl”, alone or combination with other groups, means a monocyclic or bicyclic radical of 5 to 10 ring atoms having one to three ring heteroatoms independently selected from N, O, and S, the remaining ring atoms being C.

The term “bicyclic radicals” means radicals having two rings, in which two or more ring atoms of one ring are ring carbon atoms of the other ring.

The term, “C₁₋₆ alkylsulfonyl”, “C₁₋₆ alkylsulfinyl” and “C₁₋₆ alkylthio” means C₁₋₆ alkyl-SO₂—, C₁₋₆ alkyl-SO— and C₁₋₆ alkyl-S—, respectively.

Preferred radicals for the chemical groups whose definitions are given above are those specifically exemplified in Examples.

Compounds of formula (I) can form pharmaceutically acceptable acid addition salts. Examples of such pharmaceutically acceptable salts are salts of compounds of formula (I) with physiologically compatible mineral acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The term “pharmaceutically acceptable salts” refers to such salts.

“Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “aryl group optionally substituted with an alkyl group” means that the alkyl may but need not be present, and the description includes situations where the aryl group is substituted with an alkyl group and situations where the aryl group is not substituted with the alkyl group.

“Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.

Compounds that have the same molecular Formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

The compounds of formula (I) can possess one or more asymmetric centers. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof, as well as individual epimers and mixture thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 1992).

Detailed Description

The invention is concerned with novel diazepan derivatives of formula (I),

wherein

-   -   A is aryl or heteroaryl, said aryl and said heteroaryl being         optionally substituted by one to three substituents         independently selected from the group consisting of halogen,         benzyloxy, heteroaryl-C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkoxy and         halo C₁₋₆ alkoxy, or said aryl and said heteroaryl being         optionally substituted by C₁₋₆ alkylenedioxy;     -   X is —N(R¹)(R²) or —N⁺(R¹)(R²)(R⁷);         R¹ and R² are, independently to each other, hydrogen, C₁₋₆         alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, hydroxy C₂₋₆ alkyl, C₁₋₆         alkoxy C₂₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆ alkyl,         C₇₋₁₀ bicycloalkyl, phenyl C₁₋₃ alkyl, heteroaryl C₁₋₃ alkyl,         heterocyclyl or heterocyclyl C₁₋₆ alkyl, in which the cycloalkyl         of said C₃₋₇ cycloalkyl and said C₃₋₇ cycloalkyl C₁₋₆ alkyl, the         phenyl of said phenyl C₁₋₃ alkyl, the heteroaryl of said         heteroaryl C₁₋₃ alkyl and the heterocyclyl of said heterocyclyl         and said heterocyclyl C₁₋₆ alkyl are optionally substituted by         one to three substituents independently selected from the group         consisting of R^(d); or     -   R¹ and R², together with the nitrogen atom to which they are         attached, form heterocyclyl optionally substituted by one to         three substituents independently selected from the group         consisting of R^(d), and one of the ring carbon atoms of said         heterocyclyl formed by R¹ and R² being optionally replaced with         a carbonyl group; and/or     -   one of the ring carbon atoms of the heterocyclyl formed by R¹         and R² may be a ring carbon atom of another ring which is C₃₋₇         cycloalkyl or heterocyclyl, one or two ring carbon atoms of said         another ring being optionally replaced by a carbonyl group, and         said another ring being optionally substituted by C₁₋₆ alkyl;     -   R³ and R⁴ are, independently to each other, hydrogen, hydroxy,         C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆         alkyl, C₁₋₆ alkoxycarbonyl, carboxyl, hydroxy-C₁₋₆ alkyl, C₁₋₆         alkoxy-C₁₋₆ alkyl, halogen or halo C₁₋₆ alkyl; or     -   R³ and R⁴, together with the carbon atom to which they are         attached, form C₃₋₇ cycloalkyl or heterocyclyl optionally         substituted by one to three substituents independently selected         from the group consisting of C₁₋₄ alkyl, halo C₁₋₄ alkyl and         halogen; or         R¹ is hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, hydroxy         C₁₋₆ alkyl, C₁₋₆ alkoxy C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇         cycloalkyl C₁₋₆ alkyl, C₇₋₁₀ bicycloalkyl, phenyl C₁₋₃ alkyl,         heteroaryl C₁₋₃ alkyl, heterocyclyl or heterocyclyl C₁₋₆ alkyl,         in which the cycloalkyl of said C₃₋₇ cycloalkyl and said C₃₋₇         cycloalkyl C₁₋₆ alkyl, the phenyl of said phenyl C₁₋₃ alkyl, the         heteroaryl of said heteroaryl C₁₋₃ alkyl and the heterocyclyl of         said heterocyclyl and said heterocyclyl C₁₋₆ alkyl are         optionally substituted by one to three substituents         independently selected from the group consisting of R^(d);     -   R³is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆         alkyl, halogen or halo C₁₋₆ alkyl;     -   R² and R⁴, together with the nitrogen atom to which R² is         attached, the carbon atom to which R⁴is attached and the C₁₋₂         alkylene between said nitrogen atom and said carbon atom, if         any, form heterocyclyl optionally substituted by one to three         substituents independently selected from the group consisting of         C₁₋₆ alkyl and fluorine;     -   R⁵ and R⁶ are, independently to each other, hydrogen, fluoro,         C₁₋₆ alkyl or C₃₋₇ cycloalkyl;     -   R⁷ is C₁₋₆ alkyl;     -   R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are, independently to each other,         hydrogen, C₁₋₆ alkyl or C₃₋₇ cycloalkyl;     -   R^(d) is hydroxy, cyano, NR^(a)R^(b), halogen, C₁₋₆ alkyl, halo         C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy C₁₋₆         alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkoxycarbonyl, acyl,         —C(O)NR^(a)R^(b), —NR^(a)—C(O)—R^(b), —NR^(a)—C(O)—OR^(b),         —NR^(a)—C(O)—NR^(b), —NR^(a)—SO₂—^(b), —NR^(a)—SO₂—NR^(b)R^(c),         —OC(O)NR^(a)R^(b), —OC(O)OR^(a), C₁₋₆ alkylsulfonyl, C₁₋₆         alkylsulfinyl, C₁₋₆ alkylthio, phenyl, phenyl C₁₋₃ alkyl,         heteroaryl, heteroaryl C₁₋₃ alkyl and heterocyclyl, and the         phenyl of said phenyl and said phenyl C₁₋₃ alkyl, the heteroaryl         of said heteroaryl and said heteroaryl C₁₋₃ alkyl, and the         heterocyclyl being optionally substituted by one to three         substituents independently selected from the group consisting of         hydroxy, cyano, NR^(a)R^(b), halogen, C₁₋₆ alkyl, halo C₁₋₆         alkyl, hydroxy C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, acyl,         —C(O)NR^(a)R^(b), —NR^(a)—C(O)—R^(b), —NR^(a)—C(O)—OR^(b),         —NR^(a)—C(O)—NR^(b), —NR^(a)—SO₂—R^(b), —NR^(a)—SO₂—NR^(b)R^(c),         —OC(O)NR^(a)R^(b), —OC(O)OR^(a), C₁₋₆ alkylsulfonyl, C₁₋₆         alkylsulfinyl and C₁₋₆ alkylthio, and one or two ring carbon         atoms of the heterocyclyl being optionally replaced with a         carbonyl group;     -   R^(a), R^(b) and R^(c) are independently hydrogen or C₁₋₆ alkyl;     -   n is an integer of 0 to 3;     -   m is an integer of 0 to 3;     -   m+n is an integer of 1 to 5;         or prodrugs or pharmaceutically acceptable salts thereof.

While the broadest definition of this invention is described before, certain compounds of formula (I) are preferred.

A preferred compound of the invention is a compound of formula (I), wherein A is phenyl optionally substituted by one to three substituents independently selected from the group consisting of halogen, benzyloxy, heteroaryl-C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkoxy and halo C₁₋₆ alkoxy, or A is phenyl optionally substituted by C₁₋₆ alkylenedioxy. More preferably, A is phenyl substituted by one or two halogen atoms independently selected from the group consisting of chlorine and fluorine. Further more preferably, A is phenyl substituted by two halogen atoms independently selected from the group consisting of chlorine and fluorine at its 3,4 or 3,5 position.

Another preferred compound of the invention is a compound of formula (I), wherein X is —N(R¹)(R²). Preferably, at least one of R¹ and R² is other than hydrogen. R¹ is preferably hydrogen, C₁₋₆ alkyl, or hydroxy C₂₋₆ alkyl, more preferably hydrogen or C₁₋₆ alkyl, especially hydrogen, and R² is preferably C₃₋₇ cycloalkyl, heterocyclyl, heterocyclyl C₁₋₆ alkyl, C₇₋₁₀ bicycloalkyl, hydroxy C₂₋₆ alkyl or C₁₋₆ alkoxy C₂₋₆ alkyl, especially heterocyclyl, in which the cycloalkyl and the heterocyclyl of said heterocyclyl and said heterocyclyl C₁₋₆ alkyl are optionally substituted by one or two substituents independently selected from the group consisting of C₁₋₆ alkyl, hydroxy, heteroaryl and C₁₋₆ alkoxy. When X is —N(R¹)(R²), m+n is preferably an integer of 1 or 2, especially 1, and/or R³, R⁴, R⁵ and R⁶ are preferably hydrogen.

In this group ii), preferably A is phenyl optionally substituted by one to three substituents independently selected from the group consisting of halogen, benzyloxy, heteroaryl-C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkoxy and halo C₁₋₆ alkoxy, or A is phenyl optionally substituted by C₁₋₆ alkylenedioxy. More preferably, A is phenyl substituted by one or two halogen atoms independently selected from the group consisting of chlorine and fluorine. Further more preferably, A is phenyl substituted by two halogen atoms independently selected from the group consisting of chlorine and fluorine at its 3,4 or 3,5 position.

Another preferred compound of the invention is a compound of formula (I), wherein X is —N(R¹)(R²), and R¹ and R², together with the nitrogen atom to which they are attached, form heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of R^(d), and one of the ring carbon atoms of said heterocyclyl formed by R¹ and R² being optionally replaced with a carbonyl group; and/or one of the ring carbon atoms of the heterocyclyl formed by R¹ and R² may be a ring carbon atom of another ring which is C₃₋₇ cycloalkyl or heterocyclyl, one or two ring carbon atoms of said another ring being optionally replaced by a carbonyl group, and said another ring being optionally substituted by C₁₋₆ alkyl.

The heterocyclyl formed by R¹ and R², together with the nitrogen atom to which they are attached, is preferably a mono-cyclic radical of five or six ring atoms in which one more ring atom, in addition ot the nitrogen atom, may be a heteroatom independently selected from N, O and S(O)_(n) (where n is an integer from 0 to 2), such as piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl or 1,1-dioxo-thiomorphlinyl. The heterocyclyl formed by R¹ and R², together with the nitrogen atom to which they are attached, is preferably piperidyl or pyrrolidinyl.

More preferably, the heterocyclyl formed by R¹ and R², together with the nitrogen atom to which they are attached, is optionally substituted by one or two substituents independently selected from the group consisting of hydroxy, phenyl and hydroxy C₁₋₆ alkyl, and/or

one of the ring carbon atoms of the heterocyclyl formed by R¹ and R² may be a ring carbon atom of another ring which is five or six membered mono-cyclic heterocyclyl, one or two ring carbon atoms of said another ring being optionally replaced by a carbonyl group.

In this group iii), m+n is preferably an integer of 1 to 3, and R³, R⁴, R⁵ and R⁶ are hydrogen.

Moreover, in this group iii), preferably A is phenyl optionally substituted by one to three substituents independently selected from the group consisting of halogen, benzyloxy, heteroaryl-C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkoxy and halo C₁₋₆ alkoxy, or A is phenyl optionally substituted by C₁₋₆ alkylenedioxy. More preferably, A is phenyl substituted by one or two halogen atoms independently selected from the group consisting of chlorine and fluorine. Further more preferably, A is phenyl substituted by two halogen atoms independently selected from the group consisting of chlorine and fluorine at its 3,4 or 3,5 position.

Another preferred compound of the invention is a compound of formula (I), which is

-   -   1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(4-piperidin-1-yl-butyl)-[1,4]diazepan-5-one,     -   1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one,     -   1-[(E)-3-(4-Chloro-3-fluoro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one,     -   8-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione,     -   1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[3-(4-hydroxy-4-phenyl-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one,     -   (+/−)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[3-(3-hydroxy-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one,     -   8-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one,     -   1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[3-(tetrahydro-pyran-4-ylamino)-ethyl]-[1,4]diazepan-5-one,     -   (S)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[3-(2-hydroxymethyl-pyrrolidin-1-yl)-ethyl]-[1,4]diazepan-5-one,         or     -   1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(2-pyrrolidin-1-yl-ethyl)-[1,4]diazepan-5-one,         or     -   1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[3-((−,         cis)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one.         or     -   1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[3-(3-hydroxy-4,4-dimethyl-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one,         or     -   (cis)-1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[3-(3-hydroxy-5-methyl-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one,         or     -   1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[2-hydroxy-3-(3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one,         or     -   1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[(S)-2-hydroxy-3-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one,         or     -   1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[(S)-2-hydroxy-3-(3-hydroxy-4,4-dimethyl-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one,         or     -   1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[(S)-2-hydroxy-3-(cis-3-hydroxy-5-methyl-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one,         or     -   1-[(E)-3-(4-Chloro-3-fluoro-phenyl)-acryloyl]-4-[4-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-[1,4]diazepan-5-one,         or     -   (cis)-1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[4-(3-hydroxy-5-methyl-piperidin-1-yl)-butyl]-[1,4]diazepan-5-one,         or     -   1-[(E)-3-(3-Chloro-phenyl)-acryloyl]-4-[3-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one,         or     -   1-[(E)-3-(5,6-Dichloro-pyridin-3-yl)-acryloyl]-4-[3-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one,         or     -   1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[3-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one,         or     -   1-[(E)-3-(3-Chloro-phenyl)-acryloyl]-4-[3-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one,         or     -   1-[(E)-3-(5,6-Dichloro-pyridin-3-yl)-acryloyl]-4-[3-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one.         General Synthetic Procedures

The compounds of the present invention can be prepared, for example, by the general synthetic procedures described below. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Starting materials are either commercially available or can be prepared by methods known in the art.

In Scheme 1, PG means protecting group, such as BOC(tert-butyloxy carbonyl), Z(benzyloxy carbonyl). Y¹ means bromide, iodide, mesylate or triflate, A, X, R³, R⁴, R⁵ and R⁶, m and n are as defined before. The same reactions described in scheme 1 can be performed with 1 being substituted with R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³, as defined before.

Protected 5-oxo-[1,4]diazepanes 1 of scheme 1 are commercially available or can be synthesized by methods known in the art (see e.g. Dickerman, S. C.; Lindwall, H. G. Piperidone chemistry. I. Synthesis of 5-homopiperazinones. Journal of Organic Chemistry (1949), 14 530-6). R⁵, R⁶ can be introduced on a suitably protected 5-oxo-[1,4]diazepanes through deprotonation at low temperature and alkylation or fluorination followed by a second deprotonation and alkylation or fluorination, or can also be synthesized from the corresponding piperazinone (see e.g. Design and synthesis of combinatorial scaffolds-diazepinone and homopiperazine. Sun, Chung-Ming. Department of Chemistry, National Dong-Hwa University, Hualien, Taiwan. Letters in Drug Design & Discovery (2005), 2(1), 48-50). Y¹ activated building block 2 is commercially available or can be synthesized as described below. The corresponding none activated precursor amines can be synthesized from acids via amide and reduction with methods known in the art, followed optionally by quaternisation. The corresponding acids are commercially available or can be synthesized from epsilon-hydroxy acids via R³ and then R⁴ alkylation followed optionally by [CH₂]_(m-1) elongation. The Y¹ for the amine can then be introduced by activation of the epsilon-hydroxyl group to Y¹ (Y¹═Cl, e.g. reaction of the alcohol with thionyl chloride in THF 0° C. to 50° C. gives the corresponding chloride). Deprotonation of protected 5-oxo-[1,4]diazepanes 1 in solvents like DMF with e.g. NaH as base at 0° C. to RT followed by reaction with building block 2 at 0° C. to 75° C., preferably 50° C. gives the protected intermediate 3 (step a). Deprotection (e.g. for BOC protected 3, with HCl in dioxane, in CH₂Cl₂ and methanol as solvents) gives intermediate 4 as hydrochloride salt (step b) which can be coupled with all possible acids 5 to give the final compound I (step c). Acid 5 can be activated e.g. with oxalyl chloride and catalytic amount of DMF to the ciannamic acid chloride and then reacted with amine 4 in the presence of a base like triethyl amine, or CDI activation DCC, HATU coupling are possible alternatives. Acids 5 can be synthesized from the corresponding aldehydes, or from the corresponding alcohols via oxidation and subsequent Wittig reaction or subsequent Knoevenagel reaction with malonate.

The compounds I with X═—N(R¹)(R²) can optionally be converted to X═—N⁺(R¹)(R²)(R³) with R³-halogenide in a solvent like methanol as described in scheme 5 shown below.

In Scheme 2, Y¹ means bromide, iodide, mesylate or triflate, A, R¹, R², R³, R⁴, R⁵ and R⁶, m and n are as defined before. The same reactions described in scheme 2 can be performed with 1 being substituted with R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³, as defined before.

The free 5-oxo-[1,4]diazepane 1 of scheme 2 is commercially available. R⁵, R⁶ can be introduced on a suitable protected 5-oxo-[1,4]diazepanes through deprotonation at low temperature and alkylation or fluorination followed by a second deprotonation and alkylation or fluorination, or can also be synthesized from the corresponding piperazinone (see e.g. Design and synthesis of combinatorial scaffolds-diazepinone and homopiperazine. Sun, Chung-Ming. Department of Chemistry, National Dong-Hwa University, Hualien, Taiwan. Letters in Drug Design & Discovery (2005), 2(1), 48-50). Acids 2 can be synthesized from the corresponding alcohols or aldehyde (via oxidation, for the alcohols) followed by Wittig reaction. Acid 2 can then be activated e.g. with oxalyl chloride and catalytic amount of DMF to the ciannamic acid chloride and then reacted with 5-oxo-[1,4]diazepanes 1 in the presence of a base like triethyl amine, alternatively CDI activation of the acid 2 or DCC or HATU coupling is possible to give intermediate 3 (step a). Y¹ activated Weinreb building blocks 4a or 8a are synthesized from the corresponding acids by treatment with N,O-dimethyl-hydroxyl-amine-hydrochloride with EDCI and HOBT in CH₂Cl₂ at 0° C. to room temperature. The acids are commercial available or can be synthesized from epsilon-hydroxy acids via R³, R⁴ alkylation followed optionally by [CH₂]_(m-1) elongation and activation of the hydroxyl group to Y¹. The elongation reaction can also lead to aldehydes, which can be transformed to acetals 4b. Y¹ activated acetals are also commercial available. Deprotonation of the 5-oxo-[1,4]diazepanes 3 in the presence of 4a, 4b or 8a, 8b in solvents like THF with e.g. NaH as base at 0° C. to RT and then at 50° C. to 75° C. gave intermediate 5a, 5b or 9a, 9b respectively (step b or e). In case of 3-bromo-N-methoxy-N-methyl-propionamide 4a, the first equivalent of NaH is forming the corresponding acrylamide which reacts after additional addition of NaH to the final amide 5a. An LAH— solution, preferable in THF was added to the cooled (preferable at −30° C.) suspension of amide 5a or 9a. After 5 to 15 min, the reaction was cooled (−78° C.) and quenched with acetone and acetic acid to give aldehyde 6 or 10. Aldehydes 6 and 10 are also received from acetal-protected 5b or 9b after cleavage with e.g. formic acid in a mixture of toluene water (step c or f). Reductive amination with R¹R²NH in CH₂Cl₂ with a slight excess of acetic acid and NaHB(OAc)₃ at room temperature gives the final compounds I (step d or g).

The compounds I with X═—N(R¹)(R²) can optionally be converted to X═—N⁺(R¹)(R²)(R³) with R³-halogenide in a solvent like methanol as described in scheme 5 shown below.

In Scheme 3, Y¹ means bromide, iodide, mesylate or triflate, Y¹ can be additionally tosylate, Y² is chloride or ester, or when m is 1, R³, together with Y² forms epoxy group or —O—C(CH₃)₂—O— group, Y² can be additionally bromide or iodide, A, X, R¹, R², R³, R⁴, R⁵ and R⁶, m and n are as defined before. The same reactions described in scheme 3 can be performed with 1 being substituted with R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³, as defined before.

The acylated 5-oxo-[1,4]diazepanes 1 of scheme 3 (corresponds to compound 3 described in scheme 2) can be reacted in two ways to the final compound I. Either directly, where building block 1 was deprotonated e.g. with NaH or potassium tert-butylate in DMA or THF at 0° C. to 65° C. and then reacted with the activated amine 2 (step a). Deprotonation can be carried out with potassium tert-butylate, and THF can be also used as a solvent. Amine 2 is commercially available or can be synthesized by methods known in the art. Amines can be synthesized from acids via amide and reduction to the corresponding amines 2 with methods known in the art followed optionally by quaternisation. The corresponding acids are commercial available or can be synthesized from suitably protected epsilon-hydroxy acids via R³ and then R⁴ alkylation followed optionally by [CH₂]_(m-1) elongation or R³ modification (e.g. reduction of the ester to the alcohol and protecting it orthogaonal to the epsilon-hydroxy group or alkylation of the alcohol) and activation of the deprotected epsilon-hydroxyl group to Y¹ (Y¹═Cl, e.g. reaction of the alcohol with thionyl chloride in THF 0° C. to 50° C. gives the corresponding chloride, followed optionally by Finkelstein reaction to the corresponding Y¹═Br or Y¹═I). Amine 2 can also be synthesized from building block 3 when Y² is more reactive than Y¹ (e.g. Y²═Y¹ but preferred reactivity through steric control with the corresponding amine 6). Another possibility is to react the deprotonated acylated 5-oxo-[1,4]diazepanes 1 with building block 3, where the Y¹ and Y² are groups as indicated in the scheme 3 to give intermediate 4 (step b). Building block 3 is commercial available or can be synthesized from epsilon-hydroxy acids via R³ and then R⁴ alkylation followed optionally by [CH₂]_(m-1) elongation, optionally by introduction of Y², which is a group with a lower reactivity than Y¹. Transformation of the epsilon hydroxyl group to Y¹ gives 3. For Y²=chloride, a better leaving group has to be synthesized via Finkelstein reaction (NaI in 2-butanone at 95° C.) to give compound 5 (step c). In case for Y²=ester, sodium borohydride reduction gives the alcohol, which is transferred to the chloride (methansulfonyl chloride/Et₃N in CH₂Cl₂) to give 5 (Y²═Cl) (step c). Chloride can optionally be transformed to the iodide 5 (Y²═I) under Finkelstein conditions. Reaction of 5 with an optionally excess of amine 6 in the presence of NaI (for Y²═Cl) or optionally of Et₃N, in DMF or DMA gives the final compound I (step d).

In case m is 1, R³, together with Y² forms epoxy group and Y¹═Br or I, building block 3 is an epoxide which reacts with 5-oxo-[1,4]diazepan 1 as described above to the corresponding epoxide 5 (R³ and Y² form epoxy group and m is 1). Reaction with amine 6 in ethanol or with Cs₂CO₃ in DMF or DMA at RT to 80° C. gives the final compound I, which optionally can be separated on a chiral column in the enantiomers. Epoxides 3 are commercially available or can be synthesized from the corresponding alkenes with e.g. m-chloroperbenzoic acid in dichloromethane. For the chiral synthesis, the corresponding commercially available or synthesized chiral 2,2-dimethyl-[1,3]dioxalane 3 (—R³—Y²— is —O—C(Me)₂-O—) was used. Acetal 4 (R³ and Y² form —O—C(Me)₂-O—) can be cleaved (Dowex H⁺ in methanol under reflux), mono mesylated (4, R³═OH, Y²═OMes) and in situ cyclised to the epoxide 5 (R³ and Y² form epoxy group and m is 1; e.g. mesylchlorid and excess collidine, followed by addition of NaH in DMA at 0° C.). Epoxide 5 was then reacted with amine 6 in ethanol or with Cs₂CO₃ in DMF or DMA at 0° C. to 80° C. to give the final compound I. Compound I can further be modified (e.g. R³═COOC₁₋₆ alkyl) by hydrolisis with LiOH in THF/ethanol to I (e.g. R³═COO⁻Li⁺) or reduction with NaBH₄ in EtOH or NaBH₄ in THF to I (e.g. R³═CH₂OH). The amines HNR¹R² 6 are commercial available or can be synthesized by methods known in the art. The R^(d)-substitution can be introduced or manipulated on the appropriate protected amine NR¹R². Hydroxy groups can be synthesized from ketones, both can be transformed either to mono or di-halogenides. The ketone group in the protected NR¹R² can be reacted with the metal reagent of C₁₋₆ alkyl, phenyl, phenyl C₁₋₃ alkyl, heteroaryl, heteroaryl C₁₋₃ alkyl and heterocyclyl which are optionally substituted to give the tertiary alcohol. The tertiary alcohol can optionally be eliminated and the double bond hydrogenated to give the corresponding substituted protected NR¹R². Alternatively, the ketone group in the protected NR¹R² can be converted to an allylic alcohol via a two step sequence of Wittig reaction to the exomethylene and subsequent allylic oxidation using a suitable reagent e.g. SeO₂ to afford the allylic alcohol (as described in J. Org. Chem. 2001, 66, 2487). The resulting allylic alcohol can then be cyclopropanated (e.g with Et₂Zn/CH₂Cl) to afford the cyclopropanated derivatives, which in turn can be reduced catalytically (e.g. Pt₂O and hydrogen) to afford gem-dimethyl piperidines. Alternatively the cyclopropyl can be introduced directly by double alkylation of the alpha-position of the ketone group in the protected NR¹R² by deprotonation with a suitable base e.g. tBuOK, and reaction with a double nucleophile as described in Tet. Lett. 1984, 25, 5501. Subsequent reduction of the ketone with e.g. NaBH₄ affords the alcohol derivatives. Additionally, spirocyclic derivatives can be prepared from such a suitably protected ketone bearing NR¹R² as described in J. Org. Chem. 1996, 61, 22, 7650-7651 and J. Med. Chem. 1995, 38, 3772-3779. Substitution on the C₁₋₆ alkyl, phenyl, phenyl C₁₋₃ alkyl, heteroaryl, heteroaryl C₁₋₃ alkyl and heterocyclyl can be further manipulated as discussed below. Cyano groups can be synthesized from amides. R^(a)R^(b) in the NR^(a)R^(b)-substituent can be introduced through orthogonal protection strategy. C₁₋₆ alkyl, halo C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, acyl can be introduced through enolate alkylation of keton or esters followed by optionally reduction of the ketone to the corresponding methylene group. C(O)NR^(a)R^(b) groups are synthesized from acids and amines HNR^(a)R^(b), —NR^(a)—C(O)—R^(b) from amines and acids HOOC—R^(b), —NR^(a)—C(O)—OR^(b) from amines and chloro-formates Cl—C(O)—OR^(b), —NR^(a)—C(O)—NR^(b) from amines and isocyanates OCN—R^(b) (which can also be used to generate cyclic ureas as described in WO2005/101989 (A2) where R^(b) bears a leaving group), —NR^(a)—SO₂—R^(b) from amines and sulfonyl chlorides ClSO₂—R^(b), —NR^(a)—SO₂—NR^(b)R^(c) from amines and sulfamoyl chlorides which can be synthesized in acetonitrile with R^(b)R^(c)NH and sulfuryl chloride at 0° C. to 65° C. In case R^(a) is an alkyl side chain, this group may be introduced with NaH, R^(a) halide in DMF at 0° C. to room temperature. The R^(d)-substitution can also be introduced or transformed on the appropriate protected amine NR¹R² with hydroxy groups: the hydroxy group and isocyanates OCN—R^(b) gives —OC(O)NR^(a)R^(b), the hydroxy group and chloro-formates Cl—C(O)—OR^(b) gives —OC(O)OR^(b), the hydroxy group can be akylated. The hydroxy group can be mesylated and reacted with C₁₋₆ alkylthiol, which can optionally be oxidized to C₁₋₆ alkylsulfonyl- or C₁₋₆ alkylsulfinyl-substituents. The mesylate in NR¹R² can also be reacted with amines HNR^(a)R^(b), with NH of heteroaryls or heterocyclyl in the presence of a base. Alternatively, the R^(d)-substitution can also be introduced or transformed on the appropriate protected amine NR¹R² bearing an ester group, which on reaction with hydrazine at reflux in EtOH affords the corresponding hydrazide which can be then condensed with alkoxyamidines to afford 1,2,4-triazoloyl derivatives. Esters can also be reacted with N-hydroxy-amidines in THF with e.g. NaH as base to [1,2,4]oxadiazols. Acids can be reacted with hydrazides to di acylated hydrazides which can be cyclised with phosphoroxy chloride in acetonitrile to [1,3,4]oxadiazol. Nitriles can be transformed to the corresponding N-hydroxy-amidines and then transformed to the [1,2,4]oxadiazols. Additionally, the appropriately protected amine NR¹R² derivatives can be prepared from the corresponding pyridine derivatives by reduction to the piperidine under catalytic hydrogenation conditions e.g. Pt₂O or Pd/C and hydrogen as described in WO2004/094371(A2) or by partial reduction of the corresponding pyridinium compounds (prepared by alkylation of the pyridine with a suitable alkylating reagent e.g. benzylbromide) with a suitable reducing agent e.g. NaBH₄. The resulting olefins can then be hydroborated e.g. with borane and subsequent oxidative work up to introduce hydroxy groups stereospecifically as described in Tet. Lett. 2000, 41, 5817. Piperidines can also be prepared via condensation of benzylamine, with formaldehyde and the required ketone as described in WO 01/00577A2. The resulting ketopiperidines can be further derivatised as described previously.

The compounds I with X═—N(R¹)(R²) can optionally be converted to X═—N⁺(R¹)(R²)(R³) with R³-halogenide in a solvent like methanol as described in scheme 5 shown below.

In Scheme 4, PG means protecting group, such as BOC(tert-butyloxy carbonyl), Z(benzyloxy carbonyl). X is Cl and A, R¹, R², R³, R⁴, R⁵ and R⁶, m and n are as defined before. The same reactions described in scheme 4 can be performed with 1 being substituted with R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³, as defined before.

An alternative method for the preparation of 5-oxo-[1,4]diazepanes I in which R² and R⁴ are attached to form a heterocyclyl starts from a suitably protected ethylene diamine 1 (e.g. tert-butylcarbonyl), which after reductive amination with aldehyde of the type 2 under standard conditions (CH₂Cl₂, AcOH, NaBH(OAc)₃) will generate amine 3 (step a in Scheme 4). In case of n=0, ketone 2 (e.g. benzylpiperidone) can be reductively aminated as described before or the intermediate imine can be treated with a metalo-R³, to introduce R³. Coupling of this amine 3 with an acryloyl chloride derivative 4 (Schotten-Baumann conditions) affords acrylamide derivative 5 (step b) which can then be cyclised to the diazepan 6 by treatment with a base in a polar solvent e.g. tBuOK in DMF (step c). For the introduction of R⁶, 6 (R⁶═H), can be deprotonated at low temperature and then be alkylated or fluorinated, to give the corresponding 6. This can then be elaborated as described earlier (e.g. scheme 1, compound 3 to I) to the desired final compounds I (step e and f).

This reaction sequence can also be used with amines 2, where R⁴ and R² do not form a heterocyclyl ring.

The compounds I with X═—N(R¹)(R²) can optionally be converted to X═—N⁺(R¹)(R²)(R³) with R³-halogenide in a solvent like methanol as described in scheme 5 shown below.

In Scheme 5, A, R¹, R², R³, R⁴, R⁵ and R⁶, m and n are as defined before. The same reactions described in scheme 5 can be performed with 1 being substituted with R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³, as defined before.

In Scheme 6, Y¹ is bromide, iodide, mesylate, tosylate or triflate, A, X, R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ and n are as defined before.

In case R³═COOC₁₋₆ alkyl, m=1, building block 2 can be an acrylate which reacts with 5-oxo-[1,4]diazepane 1 in the presence of NaH in DMF or DMA at 0° C. to RT to give intermediate 3. Reaction with amine 4 in acetonitrile with Cs₂CO₃ at RT gives the final compound I, which optionally can be separated on a chiral column in the enantiomers. Amines 4 are commercial available or can be synthesized as described above. R⁴ can be introduced at low temperatures via deprotonation and alkylation with a R⁴-halide. Compound I can further be modified (e.g. R³═COOC₁₋₆ alkyl) by hydrolysis with LiOH in THF/ethanol to I (e.g. R³═COO⁻Li⁺) or reduction with NaBH₄ in EtOH or LiBH₄ in THF to I (e.g. R³═CH₂OH).

[1,4]-Diazepan-5-ones intermediates of general formula 1 can be synthesized from 1-benzylpiperidin-4-ones of formula 2, as illustrated in Scheme 7. Compounds of formula 2 are either commercially available or can be synthesized according to methods described in the art (e. g., Heterocycles 1987, 26, 2165). Schmidt rearrangement or Beckmann rearrangement of 2 (J. Org. Chem. 1949, 14, 530) leads to 1-benzyl-[1,4]-diazepan-5-one 3. In the case of unsymmetrically substituted piperidin-4-ones 2, the rearrangement reaction may lead to a mixture of regioisomeric products, which can be separated e. g., by crystallization or chromatography. Finally, 1 is obtained from 3 through hydrogenation at pressures of 1-10 bar, preferably at room temperature, in a solvent such as methanol or ethanol, in the presence of a suitable catalyst such as palladium on activated charcoal.

In Scheme 7, R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are as defined before. [1,4]-diazepan-5-ones of general formula 1 can also be synthesized as described in Scheme 8 from N-(benzyloxycarbonyl)-β-amino acid esters 2 (R^(a)=methyl or ethyl). Compounds of general formula 2 are either commercially available or may be synthesized according to literature methods (e. g., Tetrahedron 2005, 61, 8372). Reaction of 2 with appropriately substituted 2,2-dioxo[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl esters 3 (Bioorg. Med. Chem. Lett. 2006, 16, 1207) in the presence of a base, e. g., potassium tert-butylate or sodium hydride, in a solvent such as 2,2-dimethylpropan-1-ol or N,N-dimethylformamide, at temperatures between 0° C. and 60° C., produces intermediate 4. Cleavage of the Boc protective group (e. g., with hydrogen chloride in 1,4-dioxane or trifluoroacetic acid in dichloromethane), followed by intramolecular ring closure (in the presence of a base such as potassium carbonate, in a solvent such as methanol or ethanol, at temperatures between 0° C. and the boiling point of the solvent), furnishes the [1,4]-diazepan-5-one-1-carboxylic acid benzyl ester 5. The benzyl carbamate group of 5 is removed by hydrogenation at pressures of 1-10 bar, preferably at room temperature, in the presence of a suitable catalyst such as palladium on activated charcoal, thereby leading to 1.

In Scheme 8, R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are as defined before. [1,4]-diazepan-5-ones of general formula 1 can also be synthesized as described in Scheme 9 from Boc-protected 1,2-diaminoethane derivative 2. Reaction of 2 with 2-propenoic acid ester derivative 3 (R^(a)=methyl or ethyl) in the presence of a base, e. g., sodium hydride or potassium tert-butylate, in a solvent such as N,N-dimethylformamide, leads to [1,4]-diazepan-5-one-1-tert-butyl ester 4. Substituents R⁶ can be introduced as described in Scheme 1, leading to 5. Finally, cleavage of the tert-butyl carbamate moiety in 5 (e. g., with hydrogen chloride in 1,4-dioxane or trifluoroacetic acid in dichloromethane) leads to 1.

In Scheme 8, R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are as defined before.

Compounds of formula I can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbants or eluent). The invention embraces all of these forms.

As described above, the compounds of formula (I) are CCR-2 receptor antagonists, with some antagonist activity also at CCR-3 and CCR-5. These compounds consequently prevent migration of various leukocyte populations through the blockade of CCR-2 stimulation. They therefore can be used for the treatment and/or prevention of inflammatory and/or allergic diseases, such as peripheral arterial occlusive disease, critical limb ischemia, vulnerable atherosclerotic plaque patients, unstable angina, congestive heart failure, left ventricular hypertrophy, ischemia reperfusion injury, stroke, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, irritable Bowel Disease, Crohns' disease, multiple sclerosis, neuropathic pain, atherothrombosis and/or burns/ulcers in Diabetes/CLI, and asthma.

Prevention and/or treatment of inflammatory diseases, particularly peripheral arterial occlusive diseases or atherothrombosis is the preferred indication.

The invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable excipient.

The invention likewise embraces compounds as described above for use as therapeutically active substances, especially as therapeutically active substances for the treatment and/or prophylaxis of inflammatory and/or allergic diseases, particularly as therapeutically active substances for the treatment and/or prophylaxis of peripheral arterial occlusive disease, critical limb ischemia, vulnerable atherosclerotic plaque patients, unstable angina, congestive heart failure, left ventricular hypertrophy, ischemia reperfusion injury, stroke, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, irritable Bowel Disease, Crohns' disease, multiple sclerosis, neuropathic pain, atherothrombosis, burns/ulcers in Diabetes/CLI, and allergy, asthma.

The invention also relates to the use of compounds as described above for the preparation of medicaments for the therapeutic and/or prophylactic treatment of inflammatory and/or allergic diseases, particularly for the therapeutic and/or prophylactic treatment of peripheral arterial occlusive disease, critical limb ischemia, vulnerable atherosclerotic plaque patients, unstable angina, congestive heart failure, left ventricular hypertrophy, ischemia reperfusion injury, stroke, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, irritable Bowel Disease, Crohns' disease, multiple sclerosis, neuropathic pain, atherothrombosis, burns/ulcers in Diabetes/CLI, and asthma. Such medicaments comprise a compound as described above.

The invention also relates to the process and the intermediates for manufacturing the compounds of formula (I) as well as the process for manufacturing the intermediates.

CCR-2 receptor antagonistic activity by the compounds of the present invention can be demonstrated by the following assays.

Receptor Binding Assays

Binding assays were done with membranes from CHOK1-CCR2B-A5 cells (Euroscreen) stably overexpressing the human CCR2B.

Membranes were prepared by homogenizing the cells in 10 mM Tris pH 7.4, 1 mM EDTA, 0.05 mM benzamidine, leupeptin 6 mg/L and separating the debris at 1000 g. The membranes were then isolated at 100000 g in 50 mM Tris pH 7.4, MgCl₂ 10 mM, EGTA 1 mM, glycerol 10%, benzamidine 0.05 mM, leupeptine 6 mg/l.

For binding, CCR2 antagonist compounds were added in various concentrations in 50 mM HEPES pH 7.2, 1 mM CaCl₂, 5 mM MgCl₂, 0.5% BSA, 0.01% NaN₃, together with 100 pM ¹²⁵I-MCP-1 (PerkinElmer, 2200 Ci/mmol) to about 5 fMol CCR2 membranes and incubated for 1 hour at room temperature. For unspecific control 57.7 nM MCP-1 (R&D Systems or prepared at Roche) was added. Membranes were harvested through GF/B (glass fiber filter; PerkinElmer) plates, equilibrated with 0.3% polyethylenimine, 0.2% BSA, air dried and binding was determined by counting in a topcounter (NXT Packard). Specific binding was defined as total binding minus nonspecific binding and typically represents about 90-95% of the total binding. Antagonist activity is indicated as inhibitor concentration required for 50% inhibition (IC₅₀) of specific binding.

Calcium Mobilization Assay

CHOK1-CCR2B-A5 cells (from Euroscreen) stably overexpressing the human chemokine receptor 2 isoform B were cultured in Nutrient Hams F12 medium supplemented with 5% FBS, 100 U/ml penicillin, 100 μg/ml streptomycin, 400 μg/ml G418 and 5 μg/ml puromycin.

For the assay cells were grown overnight in 384-well black clear flat bottom polystyrene plates (Costar) at 37° C. at 5% CO₂. After washing with DMEM, 20 mM Hepes, 2.5 mM probenecid, 0.1% BSA (DMEM assay buffer) cells were loaded with 4 μM Fluo-4 in the same DMEM assay buffer for 2 hours at 30° C. Excess dye was removed and cells were washed with DMEM assay buffer. 384-well compound plates were prepared with DMEM assay buffer/0.5% DMSO with or without various concentrations of test compounds. Usually compounds were tested for agonist and antagonist activity.

Test compounds were added to the assay plate and agonist activity was monitored as fluorescence for 80 seconds with a FLIPR (488 nm excitation; 510-570 nm emission; Molecular Devices). After 20-30 min. of incubation at 30° C., 20 nM MCP-1 (R&D; Roche) was added and fluorescence was monitored again for 80 seconds. Increases in intracellular calcium are reported as maximum fluorescence after agonist exposure minus basal fluorescence before exposure. Antagonist activity is indicated as inhibitor concentration required for 50% inhibition of specific calcium increases.

The compounds I of the present invention exhibit IC50 values in the Ca mobilisation assay of 1 nM to 10 μM, preferably 1 nM to 1.5 μM for CCR2. The following table shows measured values for some selected compounds of the present invention.

Example Number IC50(μM) 1 0.681 3 1.245 4 0.15 6 1.311 7 1.289 9 0.14 10 0.073 11 0.363 13 0.727 17 0.756 25 1.017 27 0.248 32 1.466 33 0.343 34 1.394 36 0.725 37 0.265 38 0.121 39 0.538 40 0.611 41 1.184 44 0.646 45 0.013 46 0.333 47 0.193 48 0.064 49 0.51 50 0.055 51 0.046 53 0.441 54 0.747 55 0.098 56 1.077 57 0.217 58 0.546 59 0.014 60 0.023 62 0.165 63 0.503 64 0.391 65 0.197 67 0.241 69 0.185 70 0.146 71 0.566 72 0.312 74 0.175 75 0.267 76 0.219 77 0.326 78 0.444 79 0.706 80 0.263 81 0.204 82 0.297 84 0.223 85 1.17 86 1.084 87 0.315 88 0.757 91 0.148 92 0.189 96 1.136 97 1.207 99 1.216 101 1.229 102 1.025 103 0.388 104 0.598 105 0.806 106 0.523 108 1.199 109 0.521 110 0.641 111 0.335 117 0.459 120 1.143 124 0.667 134 0.6 136 0.688 138 1.261 153 0.446 154 0.373 155 0.37 157 0.703 159 0.258 160 0.232 161 0.047 162 0.319 163 0.56 164 0.544 165 0.345 166 0.212 167 0.028 169 0.255 170 0.448 171 0.995 172 0.105 175 0.096 177 0.954 178 0.201 179 0.003 180 0.319 181 0.003 183 1.227 186 0.038 187 0.385 188 1.338 189 0.008 190 0.118 191 0.025 192 0.015 193 0.644 194 0.494 195 0.453 196 0.864 198 0.739 199 1.336 201 0.656 205 0.325 208 0.78 209 1.392 210 1.136 211 0.363 212 0.437 213 0.421 214 0.592 215 0.356 216 0.726 217 1.212 219 0.045 220 0.169 221 0.478 223 0.013 224 0.014 225 0.243 226 0.464 227 0.409 228 0.149 229 0.154 230 0.215 231 0.218 232 0.091 233 0.359 235 0.112 236 0.565 238 0.054 240 0.105 241 0.765 242 0.124 243 0.133 244 0.66 246 0.421 247 0.613 248 0.226 249 1.253 250 0.812 251 0.008 252 0.12 253 0.132 254 0.108 255 0.561 256 1.074 257 0.182 258 0.375 259 0.057 260 0.009 261 0.009 262 0.004 266 0.077 267 0.214 268 0.215 269 0.619 270 0.01 271 0.055 272 0.191 273 0.313 274 0.004 275 1.093 277 1.292 278 0.54 279 0.005 280 0.021 281 0.129 282 0.212 283 0.311 284 0.717 285 0.644 287 0.848 288 0.206 289 0.296 290 0.199 291 0.404 293 1.118 296 0.298 298 0.281 300 0.981 301 0.977 303 0.257 305 0.192 306 0.391 307 0.437 309 0.016 315 0.717 316 0.755 317 0.528 318 0.707 319 0.265 320 1.489 322 1.199 324 0.215 325 0.741 326 0.999 327 0.002 328 0.028 329 0.137 330 0.006 331 0.059 332 0.002 333 0.301 334 0.004 335 0.013 336 0.003 337 0.071 338 0.553 339 1.358 340 0.019 342 0.003 343 0.011 344 0.026 347 0.864 348 0.765 355 0.982 356 0.552 357 0.385 358 0.873 359 0.807 360 0.179 361 0.226 362 0.504 363 0.073 364 0.531 370 0.341 372 1.234 374 0.58 375 0.274 376 0.416 377 0.697 378 1.239 379 1.498 381 0.236 382 0.246 383 0.198 384 0.334 385 0.31 386 0.38 387 0.584 388 0.381 389 0.323 390 1.102 392 0.054 393 0.878 394 0.551 395 0.996 397 0.944 398 1.065 399 0.72 400 0.264 401 0.092 402 0.291 404 0.095 405 0.807 407 0.264 409 0.382 411 0.199 412 0.342 413 0.077 414 0.065 415 0.027 416 0.011 418 1.473 419 0.25 420 0.052 421 0.064 422 0.07 423 0.016 424 0.119 425 0.089 426 0.07 427 0.259 428 0.113 429 0.086 430 0.352 431 0.448 432 0.016 433 0.244 434 0.14 435 0.281 436 0.746 437 0.463 438 0.369 439 0.263 440 0.103 441 0.022 442 0.085 444 0.032 445 0.354 446 0.626 447 0.092 448 0.181 450 0.243 451 0.682 453 0.033 454 0.23 455 0.106 456 0.016 457 0.283 458 0.148 459 0.267 460 0.832 461 0.614 462 0.041 463 0.348 464 0.226 465 0.376 466 0.389 467 1.16 468 0.347 469 0.061 470 0.085 471 0.043 472 0.418 473 0.051 474 0.106 475 0.02 476 0.018 477 0.313 478 0.998 479 0.232 480 0.053 481 0.009 482 0.013 485 0.075 486 0.205 487 0.014 488 0.618 490 0.026 491 0.216 492 0.026 493 0.015 494 0.006 495 0.019 496 0.007 497 0.026 498 0.011 499 0.084 500 0.451 501 0.155 502 0.253 503 0.051 504 0.316 Chemotaxis Assay

The chemotaxis assay was performed with THP1-4x cells (Mirzadegan et al. 2000, The Journal of Biological Chemistry 275, 33, 25562-25571) similar as described earlier (Kruszynski et al. 2005, Journal of Peptide Science, in press.).

THP1-4x were cultured in RPMI1640, 2 mM L-glutamine, 0.15% Na-bicarbonat, 0.25% D-glucose, 10 mM Hepes, 100 mM Na-pyruvate, 50 mM β-mercaptoethanol, 10% FBS. Isolated cells were labelled in culture medium with 2.5 μg/ml calcein-AM (Molecular Probes) for 60 minutes at 37° C. Excess calcein was removed and cells were washed in D-PBS⁺⁺, 2% FBS.

Cells (1×10⁵) with or without various concentrations of test compounds were loaded on the top of 8-μm polycarbonate filter in a 96-well-modified Boyden chamber (NeuroProbe). Beneath the filter 10 nM MCP-1 (R&D Systems; Roche) with or without test compounds or D-PBS⁺⁺, 2% FBS was placed in the corresponding well. The closed chambers were incubated for 1 hour at 37° C., 5% CO₂. Remaining cells in the top compartment were wiped off and migrated cells were measured as fluorescence in the bottom compartment in a FLUOstar (Galaxy BMG) at 485 nm excitation and 530 nm emission. Specific migration is defined as total migration towards MCP-1 minus the background migration towards D-PBS⁺⁺, 2% FBS. The ability of test compounds to antagonize CCR2-chemotaxis is reported as concentration required to inhibit 50% of specific migration (IC₅₀) towards MCP-1.

The compounds I of the present invention exhibit IC50 values in the chemotaxis assay of 1 nM to 10 μM, preferably 1 nM to 250 nM for CCR2. The following table shows measured values for some selected compounds of the present invention.

Example IC50(nM) Example 48 13 Example 59 77 Example 81 71 Example 160 101

The compounds of formula (I) and/or their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or suspensions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils. Oral administration is preferred.

The production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula I and/or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers might, however, be required in the case of soft gelatine capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.

The dosage of the compounds of formula (I) can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case (therapeutically effective amount). For adult patients a daily dosage of about 1 to 1000 mg, especially about 1 to 300 mg, comes into consideration. Depending on severity of the disease and the precise pharmacokinetic profile the compound could be administered with one or several daily dosage units, e.g. in 1 to 3 dosage units.

The pharmaceutical preparations conveniently contain about 1-500 mg, preferably 1-100 mg, of a compound of formula (I).

The following Examples serve to illustrate the present invention in more detail. They are, however, not intended to limit its scope in any manner.

EXAMPLES

Abbreviations:

AcOH=Acetic acid, BOC=t-Butyloxycarbonyl, BuLi=Butyllithium, CDI=1,1-carbonyldiimidazole, CH₂Cl₂=dichloromethane, DCE=1,2-dichloroethane, DIBALH=Di-i-butylaluminium hydride, DCC=N,N′-Dicyclohexylcarbodiimide, DMA=N,N-Dimethylacetamide, DMAP=4-Dimethylaminopyridine, DMF=N,N-Dimethylformamide, EDCI=N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, EtOAc=Ethylacetate, EtOH=Ethanol, Et₂O=Diethylether, Et₃N=Triethylamine, eq=Equivalents, HATU=O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, HOBT=1-Hydroxybenzo-triazole, Huenig's base=iPr₂NEt=N-Ethyl diisopropylamine, LAH=Lithium aluminium hydride, LDA=Lithium diisopropylamide, LiBH₄=Lithium borohydride, MeOH=Methanol, NaI=Sodium iodide, Red-Al=Sodium bis(2-methoxyethoxy)aluminium hydride, TBDMSCl=t-Butyldimethylsilyl chloride, TFA=Trifluoroacetic acid, THF=Tetrahydrofurane, quant=quantitative.

General Remarks

All reactions were performed under argon.

Intermediate 1 {4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-acetaldehyde 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one

A solution of 9.77 g (43.65 mmol) of (E)-3,4-dichlorocinnamic acid in 250 ml of CH₂Cl₂ was treated at RT with 3 drops of DMF. 4.15 ml (48.02 mmol, 1.1 eq) of oxalyl chloride in 30 ml CH₂Cl₂ were added dropwise and stirring was continued for 3 h. The solution was evaporated, redissolved in 170 ml of CH₂Cl₂, cooled (0° C.) and treated with a solution of 4.48 g (39.29 mmol, 0.9 eq) of 2,3,6,7-tetrahydro-(1H)-1,4-diazepin-5(4H)-one and 12.17 ml (87.30 mmol, 2 eq) of triethylamine in 80 ml of CH₂Cl₂. The reaction was warmed up over night to RT, then partitioned between CH₂Cl₂/MeOH 9:1 (×3)/ aqueous 10% KHSO₄, the organic phases were washed with aqueous saturated NaHCO₃ and aqueous 10% NaCl, dried over Na₂SO₄ and evaporated. The residue was dissolved and evaporated with toluene and crystallized with CH₂Cl₂/Et₂O to give 7.99 g (58%) of the title compound as white solid. MS: 312.8 (MH⁺, 2Cl).

2-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-N-methoxy-N-methyl-acetamide

A suspension of 5.01 g (16.00 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one and 3.20 g (17.60 mmol) of 2-bromo-N-methoxy-N-methyl-acetamide (intermediate 1D) in 110 ml of THF was treated at 0° C. with 0.84 g (19.20 mmol) of NaH (55% in oil) in two portions. The reaction was warmed up to RT over night and stirred for 2.5 h at 75° C. The reaction was cooled and neutralized with cold aqueous 10% KHSO₄ and extracted with EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO₃, aqueous 10% NaCl, dried over Na₂SO₄ evaporated and purified by flash silica gel column (CH₂Cl₂/MeOH 99:1 to 97.5:2.5) to yield 3.49 g (53%) of the light yellow crystalline title compound. MS: 414.1 (MH⁺, 2Cl).

{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-acetaldehyde

7.92 ml (7.92 mmol) of a LAH-solution (1.0 M in THF) was dropped to a cooled (−30° C.) suspension of 3.28 g (7.92 mmol) of 2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-N-methoxy-N-methyl-acetamide in 260 ml of THF. The reaction was stirred for 5 min at −30° C. and then cooled to −78° C. The reaction was stopped by adding first 12.8 ml (174.24 mmol) of acetone and afterwards 0.9 mL (15.84 mmol) of acetic acid. The reaction was then powered to an aqueous 10% KHSO₄ solution and extracted with ether (3×), the organic phase was dried over Na₂SO₄ evaporated dissolved in toluene and evaporated (3×) to yield 2.12 g (75%) of the title compound as light yellow foam. MS: 355.0 (MH⁺, 2Cl).

2-Bromo-N-methoxy-N-methyl-acetamide used in intermediate 1B was synthesized as follows:

2-Bromo-N-methoxy-N-methyl-acetamide

A solution of 13.90 g (100 mmol) of bromoacetic acid in 1.3 I CH₂Cl₂ was treated with 15.61 g (160 mmol) of N,O-dimethyl-hydroxylamine hydrochloride, 17.63 ml (160 mmol) of N-methylmorpholine and at 0° C. with 24.92 g (130 mmol) of EDCI and 3.07 g (20 mmol) of HOBT. The cooling bath was allowed to come to RT and after 3.5 h the reaction was extracted with aqueous 10% KHSO₄/Et₂O (3×). The organic phases were washed with aqueous saturated NaHCO₃, 10% NaCl and dried over Na₂SO₄ to yield after careful evaporation of the solvent 11.85 g (65%) of the title compound as a light yellow liquid. MS: 181.1 (M⁺, 1Br).

Intermediate 2 3-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propionaldehyde 3-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-N-methoxy-N-methyl-propionamide

A suspension of 10.02 g (32.00 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) and 6.27 g (32.00 mmol) of 3-bromo-N-methoxy-N-methyl-propionamide (intermediate 2C]) in 225 ml of THF was treated at 0° C. with 1.54 g (35.20 mmol) of NaH (55% in oil) in two portions. The suspension was stirred 4 h at RT, cooled and treated again at 0° C. with 1.54 g (35.20 mmol) of NaH (55% in oil) in two portions. The reaction was warmed up to RT over night, treated a third time at 0° C. with 1.54 g (35.20 mmol) of NaH (55% in oil) in two portions and stirred for 30 min at 50° C. After 20 h at RT, the reaction was neutralized with cold aqueous 10% KHSO₄ and extracted with EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO₃, aqueous 10% NaCl, dried over Na₂SO₄ evaporated and purified by flash silica gel column (CH₂Cl₂/MeOH 99:1 to 97.5:2.5) to yield 8.97 g (65%) of the title compound as an off-white foam. MS: 428.2 (MH⁺, 2Cl).

3-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propionaldehyde

In analogy to the procedure described in intermediate 1C, 3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-N-methoxy-N-methyl-propionamide gave the title compound as white solid. MS: 368.9 (MH⁺, 2Cl).

3-Bromo-N-methoxy-N-methyl-propionamide used in intermediate 2A] was synthesized as follows:

3-Bromo-N-methoxy-N-methyl-propionamide

In analogy to the procedure described in intermediate 1D, 3-bromopropionic acid gave the title compound as a light yellow liquid. MS: 195.9 (MH⁺, 1Br).

Intermediate 3 {4-[(E)-3-(3-Chloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-acetaldehyde 1-[(E)-3-(3-Chloro-phenyl)-acryloyl]-[1,4]diazepan-5-one

In analogy to the procedure described in intermediate 1A, (E)-3-chlorocinnamic acid and 2,3,6,7-tetrahydro-(1H)-1,4-diazepin-5(4H)-one gave the title compound as a white solid.

MS: 278.9 (MH⁺, 1Cl).

1-[(E)-3-(3-Chloro-phenyl)-acryloyl]-4-(2,2-diethoxy-ethyl)-[1,4]diazepan-5-one

A solution of 5.02 g (18.00 mmol) of 1-[(E)-3-(3-chloro-phenyl)-acryloyl]-[1,4]diazepan-5-one in 140 ml of DMA was treated at RT with 0.86 g (19.80 mmol) of NaH (55% in oil) in four portions. After 1 h 3.72 ml (21.60 mmol) of 2-bromo-1,1-diethoxy-ethane were added over 30 min. The reaction was stirred over night and heated for 1 h at 75° C. The reaction was cooled and neutralized with cold aqueous saturated NaHCO₃ and extracted with Et₂O (3×). The organic phases were washed with aqueous saturated NaHCO₃, aqueous 10% NaCl, dried over Na₂SO₄ evaporated and purified by flash silica gel column (CH₂Cl₂/MeOH 99:1 to 98:2) to yield 1.87 g (26%) of the title compound as a yellow viscous oil. MS: 395.4 (MH⁺, Cl).

{4-[(E)-3-(3-Chloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-acetaldehyde

A solution of 1.00 g (2.53 mmol) of 1-[(E)-3-(3-chloro-phenyl)-acryloyl]-4-(2,2-diethoxy-ethyl)-[1,4]diazepan-5-one in 10 ml of toluene was treated at RT with 5.22 ml formic acid and 1.5 ml water. The reaction was stirred for 1.5 h, evaporated and neutralized with aqueous saturated NaHCO₃ and extracted with Et₂O (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na₂SO₄ evaporated and purified by flash silica gel column (EtOAc) to yield 0.37 g (45%) of the title compound as off-white foam. MS: 321.3 (MH⁺, Cl).

Intermediate 4 4-(3-Piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride 5-Oxo-4-(3-piperidin-1-yl-propyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester

A solution of 8.52 g (39.75 mmol) of 5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester in 200 ml of DMA was treated at 0° C. with 2.60 g (59.62 mmol) of NaH (55% in oil) in small portions. The reaction was stirred 1 h at this temperature, then the free 1-(3-chloropropyl)piperidine in 200 ml toluene was dropped in (49.62 g (250.42 mmol, 6.3 eq.) 1-(3-chloropropyl)piperidine hydrochloride were dissolved in 262 ml of 1N NaOH and extracted with toluene (200 ml). The organic phase was dried over Na₂SO₄). The reaction was warmed up to RT and stirred over night. After 2 h at 50° C. and cooling to RT, the reaction was neutralized with water (50 ml), evaporated and then dissolved in aqueous saturated NaHCO₃/Et₂O. After reextraction with Et₂O, the organic phase was dried (Na₂SO₄), evaporated and crystallized from pentane to yield 12.08 g (90%) of the title compound as white crystals. MS: 340.2 (MH⁺).

4-(3-Piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride

A solution of 7.3 g (21.50 mmol) of 5-oxo-4-(3-piperidin-1-yl-propyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester was dissolved in 140 ml CH₂Cl₂, cooled to 0° C. and treated with 54 ml (215.03 mmol) of 4M HCl in dioxane, then warmed to RT. After 3 h, 40 ml of MeOH were added to dissolve the precipitation and stirring was continued over night. The solution was evaporated, dissolved in toluene and evaporated (2×) to yield 7.71 g (quantitative) of the title compound as a white solid. MS: 240.1 (MH⁺).

Intermediate 5 4-(2-Pyrrolidin-1-yl-ethyl)-[1,4]di-azepan-5-one-dihydrochoride 5-Oxo-4-(2-pyrrolidin-1-yl-ethyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester

In analogy to the procedure described in intermediate 4A, 5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester and 1-(2-chloro-ethyl)-pyrrolidine gave the title compound as light yellow solid. MS: 312.0 (MH⁺).

4-(2-Pyrrolidin-1-yl-ethyl)-[1,4]di-azepan-5-one-dihydrochoride

In analogy to the procedure described in intermediate 4B, 5-oxo-4-(2-pyrrolidin-1-yl-ethyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester gave the title compound as off-white powder.

MS: 212.1 (MH⁺).

Intermediate 6 6-Fluoro-3-piperidin-4-yl-1H-indole

Prepared following the protocol published in Eur. J. Med. Chem. 1987, 22, 33-43.

Intermediate 7 Piperidin-4-yl-imidazolidin-2-one

Prepared following the protocol published in WO2005/101989 (A2)

Intermediate 8 4-(5-Methyl-4H-[1,2,4]triazol-3-yl)-piperidine hydrochloride 4-(5-Methyl-4H-[1,2,4]triazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester

4-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (1.19 g, 5 mmol) was mixed with ethylacetimidate hydrochloride (0.91 g, 7 mmol) in DMF (5 ml) and Et₃N (2 ml, 15 mmol) was added. The reaction was stirred for 1 h after which time the DMF was evaporated, the residue redissolved in AcOH and 0.5 g of ammonium acetate added and the reaction heated to 100° C. for a further 3 h. The reaction was then concentrated, redissolved in CH₂Cl₂, washed with NaHCO₃, dried (Na₂SO₄) and concentrated. The residue was purified by flash column chromatography (CH₂Cl₂:MeOH 1:0-9:1) to afford the title product (0.14 g, 10%) as a colourless gum. MS: 267.4 (MH⁺)

4-(5-Methyl-4H-[1 2,4]triazol-3-yl)-piperidine hydrochloride

4-(5-Methyl-4H-[1,2,4]triazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.5 mmol) was dissolved in a solution of HCl in 1,4-dioxane (5 ml, 4 M), stirred for 2 h and then concentrated to afford the title product (0.1 g, quant) as a yellow solid. ¹H NMR (300 MHz, MeOD) δ 2.09-2.20 (2H, m), 2.36-2.40 (2H, m), 2.74 (3H, s), 3.22-3.33 (2H, m), 3.41-3.60 (3H, m).

Intermediate 9 1,3,8-Triaza-spiro[4.5]decan-4-one

Prepared following the protocol published in J. Med. Chem. 1998, 41, 25, 5084-5093.

Intermediate 10 4-Hydroxy-piperidine-4-carboxylic acid amide

Prepared following the protocol published in WO2005/110416 (A2).

Intermediate 11 1,3,8-Triaza-spiro[4.5]decane-2,4-dione

Prepared according to the procedure published in J. Org. Chem. 1996, 61, 22, 7650-7651.

Intermediate 12 4-(1H-Pyrazol-3-yl)-piperidine

Prepared according to the procedure published in WO2004/094371(A2).

Intermediate 13 trans-4-Amino-1-pyridin-2-yl-cyclohexanol

Prepared according to the procedure published in WO2005/060665(A2).

Intermediate 14 Oxa-3,8-diaza-spiro[4.5]decan-2-one

Prepared according to the procedure published in J. Med. Chem. 1995, 38, 3772-3779.

Intermediate 15 4-Oxazol-2-yl-piperidin-4-ol hydrochloride 4-Hydroxy-4-oxazol-2-yl-piperidine-1-carboxylic acid tert-butyl ester

To a solution of oxazole (1 g, 14 mmol) in anhydrous THF (10 ml) was added borane. THF complex (14 ml, 1M in THF, 14 mmol) and the mixture stirred for 1 h, after which time the reaction was cooled to −78° C. and nBuLi (9 ml, 1.6 M in hexanes, 14 mmol) added dropwise and the reaction stirred for a further 1 h. A solution of Boc-piperidone (3.2g, 16 mmol) in THF (10 ml) is then added, the reaction stirred for a further 4 h at −78° C. before allowing the reaction to reach room temperature overnight. The solvent is then evaporated, the residue redissolved in EtOAc, washed with saturated ammonium chloride solution, dried (Na₂SO₄) and concentrated. Purification by flash column chromatography (EtOAc:Heptane 3:7) affords the title product (1.9 g, 44%) as a colourless gum, contaminated with an unknown byproduct. MS: 269.2 (MH⁺)

4-Hydroxy-4-oxazol-2-yl-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.4 mmol) was dissolved in a solution of HCl in dioxane (5 ml, 4 M in dioxane) and stirred for 1 h. The reaction was then concentrated to dryness to afford the title product (0.08 g, quant) as white solid.

MS: 169.1 (MH⁺)

Intermediate 16 4-Methyl-piperidin-4-ol

Prepared according to the procedure published in J. Med. Chem. 1965, 8, 766-776.

Intermediate 17 2,8-Diaza-spiro[4.5]decane-1,3-dione

Prepared according to the procedure published in J. Med. Chem. 1995, 38, 3772-3779.

Intermediate 18 2,8-Diaza-spiro[4.5]decan-3-one

Prepared according to the procedure published in J. Med. Chem. 1995,.38, 3772-3779.

Intermediate 19 4-Hydroxy-piperidine-4-carboxylic acid amide

Prepared according to the procedure published in WO2004/043925(A2)

Intermediate 20 (+/−)-cis-(3-Methoxy-tetrahydro-pyran-4-yl)-amine

A slurry of 3-methoxy-tetrahydro-pyran-4-one (0.4 g, 3 mmol—described in WO03/093266(A1)), ammonium formate (1.9 g, 30 mmol), 10% palladium on charcoal (1 g) in water:MeOH (1:5, 6 ml) was stirred overnight after which time it was filtered through Hyflo, the mixture concentrated to remove the MeOH, the residue taken up in Et₂O, dried (Na₂SO₄) and concentrated to afford the title product (0.2 g, 49%) as a yellow oil (contaminated by 10-20% of the trans isomer). ¹H NMR (300 MHz, CDCl₃) (cis isomer) δ 1.60-1.80 (2H, m), 2.95-3.00 (1H, m), 3.22-3.43 (5H, m). 3.82-3.95 (1H, m), 4.01-4.13 (1H, m).

Intermediate 21 (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine

Prepared according to the procedure published in WO92/03464.

Intermediate 22 (2S,4S)-4-hydroxy-2-hydroxymethyl-pyrrolidine

Prepared analogously to intermediate 21 from cis-4-hydroxy-L-proline.

Intermediate 23 (2S,3S)-3-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester

Prepared from trans-3-hydroxy-L-proline (Tetrahedron Letters 2001, 42, 49, 8571-8574).

Intermediate 24 (2R,3S)-3-Hydroxy-2-hydroxymethyl-pyrrolidine

Prepared analogously to intermediate 21 from trans-3-hydroxy-L-proline.

Intermediate 25 (cis)-(rac)-3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-piperidine

Prepared via (cis)-(rac)-3,4-dihydroxy-piperidine-1-carboxylic acid benzyl ester (Tetrahedron 2006, 62, 3284-3291), followed by silylation (tert-Butyl-chloro-dimethyl-silane/imidazol in DMF) and hydrogenation (10% Pd/C, H₂ in ethanol).

Intermediate 26 (trans)-(rac)-3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-piperidine

Prepared via (trans)-(rac)-3,4-dihydroxy-piperidine-1-carboxylic acid benzyl ester (Tetrahedron 2006, 62, 3284-3291), followed by silylation (tert-Butyl-chloro-dimethyl-silane/imidazol in DMF) and hydrogenation (10% Pd/C, H₂ in ethanol).

Intermediate 27 Oxa-8-aza-spiro[4.5]decane triofluoroacetate

Prepared analogously to Bioorganic & Medicinal Chemistry Letters (2002), 12(13), 1759-1762.

Intermediate 28 4-[1,2,4]Triazol-1-yl-piperidine hydrochloride

Prepared according to the procedure published in WO2004094371.

Intermediate 29 N-Piperidin-4-yl-methanesulfonamide hydrochloride

Prepared according to the procedure published in US2005043298

Intermediate 30 (rac)-(3-Methyl-piperidin-3-yl)-methanol hydrochloride (rac)-3-Methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester

A solution of 2.42 ml (2.0 M in THF/n-heptane/ethylbenzene, 5.55 mmol) LDA in 10 ml THF was treated slowly at −78° C. with 2.00 g (7.77 mmol) ethyl 1-BOC-3-piperidinecarboxylate in 7 ml THF. After 30 min at −78° C., a solution of 2.42 ml (38.86 mmol) iodomethane was added. Over night, the solution was naturally warmed to RT, poured on aqueous 10% KHSO₄ solution and extracted with ether (3×). The organic phase was dried (Na₂SO₄) and evaporated to give 2.81 g of a mixture containing 40% of the desired compound and 60% of starting material. Repetition of the procedure above gave 2.81 g (quant.) of crude title compound containing ca 10% of staring material. MS: 272.3 (MH⁺).

(rac)-3-Hydroxymethyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester

6.14 ml (1.2 M in toluene, 7.37 mmol) of DIBALH was dropped to a dry ice cooled (−30° C.) solution of 1.00 g (3.69 mmol) crude 3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester in 2 ml of THF. The reaction was warmed up (0° C. for 1 h), continued for 3 h, cooled (−15° C.) and treated again with 0.61 ml (1.2 M in toluene, 0.74 mmol) of DIBALH. After 1 h the reaction was warmed up to 0° C. and neutralized with aqueous 10% KHSO₄ solution. The mixture was extracted with ether (3×), the organic phases were washed with a aqueous 10% NaCl solution, dried (Na₂SO₄) and evaporated to give after flash silica gel column (n-heptane/EtOAc 9:1) 0.61 g (73%) of the title compound as yellow oil. MS: 230.0 (MH⁺).

(rac)-(3-Methyl-piperidin-3-yl)-methanol hydrochloride

A solution of 0.20 g (0.87 mmol) of (rac)-3-hydroxymethyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester was dissolved in 5 ml of CH₂Cl₂, treated at 0° C. with a solution of HCl in dioxane (2.18 ml, 4 M in dioxane) and stirred for 2 h at RT. The reaction was then concentrated to dryness and re-evaporated with toluene to afford the title product (0.17 g, quant.) as white solid. MS: 130.1 (MH⁺)

Intermediate 31 (rac)-3-Methoxymethyl-3-methyl-piperidine hydrochloride (rac)-3-Methoxymethyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester

A solution of 0.37 g (1.60 mmol) of (rac)-3-hydroxymethyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (intermediate 30B) and 0.20 ml (3.20 mmol) of iodomethane in 15 ml of DMF was treated at 0° C. with 0.08 g (1.92 mmol) of NaH (55% in oil). The reaction was stirred for 2 h at 0° C., neutralized with cold aqueous 10% KHSO₄ and extracted with Et₂O (3×). The organic phases were washed with aqueous saturated NaHCO₃, aqueous 10% NaCl, dried over Na₂SO₄ evaporated and purified by flash silica gel column (n-heptane/EtOAc 95:5) to yield 0.25 g (64%) of the title compound as colorless liquid. MS: 244.1 (MH⁺).

(rac)-3-Methoxymethyl-3-methyl-piperidine hydrochloride

In analogy to the procedure described for intermediate 30C, (rac)-3-methoxymethyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester gave the title compound as white powder.

MS: 144.0 (MH⁺).

Intermediate 32 (4-Methyl-piperidin-4-yl)-methanol trifluoro-acetate

In analogy to the procedure described for intermediate 30A to 30C, ethyl 1-BOC-4-piperidinecarboxylate gave after TFA deprotection (instead of HCl in dioxane) the title compound as colorless oil.

Intermediate 33 4-Methoxymethyl-4-methyl-piperidine hydrochloride

In analogy to the procedure described for intermediate 31A to 31B, 4-hydroxymethyl-4-methyl-piperidine-1-carboxylic acid tert-butyl ester gave the title compound as white solid.

Intermediate 34 (rac)-(2-Methyl-piperidin-2-yl)-methanol hydrochloride

In analogy to the procedure described for intermediate 30A to 30C, ethyl 1-BOC-2-piperidinecarboxylate gave the title compound as light yellow powder.

Intermediate 35 (rac)-3-Hydroxymethyl-piperidin-4-ol hydrochloride 1:1 diast. Mixture A) (rac)-3-Hydroxymethyl-piperidin-4-ol hydrochloride 1:1 diast. Mixture

A solution of 1 g (4.52 mmol) (rac)-1-benzyl-3-hydroxymethyl-piperidin-4-ol (ca 1:1 diast mixture, Synthesis (1999), 11, 1937-1943) in 25 ml of MeOH was treated with a solution of HCl in dioxane (1.24 ml, 4 M in dioxane, 4.97 mmol) and 95 mg of Pd(OH)₂/C (20%) and was stirred over H₂-atmosphere for 16 h. After filtration, new catalyst was added (95 mg of Pd(OH)₂/C (20%)) and stirred over H₂-atmosphere for 2 days. After filtration, the solution was evaporated under reduced pressure to yield 0.66 g (86%) of the title compound as a ca 1:1 cis/trans mixture, MS: 132.3 (MH⁺).

Intermediate 36 (rac)-3-Methoxymethyl-piperidin-4-ol hydrochloride (rac)-4-Methoxy-3-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester and 4-Hydroxy-3-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester

A solution of 0.61 g (2.62 mmol) of (rac)-4-hydroxy-3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (Bioorganic & Medicinal Chemistry Letters (2005), 15(5), 1375-1378) in 25 ml of DMF was treated at 0° C. with 0.13 g (2.88 mmol) of NaH (55% in oil) and after 30 min slowly with 0.18 ml (2.88 mmol) of iodomethane in 14 ml of THF. The reaction was stirred for 3 h at 0° C., neutralized with cold aqueous 10% KHSO₄ and extracted with Et₂O (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na₂SO₄ evaporated and purified by flash silica gel column (n-heptane/EtOAc 95:5 to 1:1) to yield 0.073 g (11%) of 4-methoxy-3-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester as light yellow oil, MS: 260.0 (MH⁺) and 0.46 g (71%) of (rac)-4-hydroxy-3-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil containing ca 25% of (rac)-3-hydroxymethyl-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester. MS: 246.1 (MH⁺).

(rac)-3-Methoxymethyl-piperidin-4-ol hydrochloride

In analogy to the procedure described for intermediate 30C, (rac)-4-hydroxy-3-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester gave the title compound as light yellow gum, containing 25% of (rac)-(4-methoxy-piperidin-3-yl)-methanol hydrochloride. MS: 146.3 (MH⁺).

Intermediate 37 (rac)-4-Methoxy-3-methoxymethyl-piperidine hydrochloride

In analogy to the procedure described for intermediate 30C, (rac)-4-methoxy-3-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester (intermediate 36A) gave the title compound as light yellow gum. MS: 160.2 (MH⁺).

Intermediate 38 Piperidin-4-yl-carbamic acid methyl ester hydrochloride 4-Methoxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester

A solution of 4.00 g (2.00 mmol) of 4-amino-1-BOC-piperidine and 4.18 ml (3.00 mmol) of Et₃N in 50 ml of CH₂Cl₂ was treated at 0° C. with 1.62 ml (2.10 mmol) of methyl chloroformate. The reaction was stirred for 16 h at RT, neutralized with aqueous 10% KHSO₄ and extracted with CH₂Cl₂ (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na₂SO₄ evaporated and purified by flash silica gel column (n- heptane/EtOAc 1:1 to 1:2) to yield 3.30 g (64%) of the title compound as white solid. MS: 259.2 (MH⁺).

Piperidin-4-yl-carbamic acid methyl ester hydrochloride

In analogy to the procedure described for intermediate 30C, 4-methoxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester gave the title compound as white solid. MS: 158.3 (M⁺).

Intermediate 39 Methyl-piperidin-4-yl-carbamic acid methyl ester hydrochloride 4-(Methoxycarbonyl-methyl-amino)-piperidine-1-carboxylic acid tert-butyl ester

A solution of 1.01 g (3.91 mmol) of 4-methoxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester (intermediate 38A) in 15 ml of DMF was treated at 0° C. with 0.26 g (5.86 mmol) of NaH (55% in oil) and after 30 min with 1.95 ml (31.28 mmol) of iodomethane. The reaction was stirred for 16 h at RT, neutralized with cold aqueous 10% KHSO₄ and extracted with Et₂O (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na₂SO₄ evaporated and purified by flash silica gel column (n-heptane/EtOAc 1:1) to yield 0.99 g (93%) of the title compound as colorless oil. MS: 273.1 (MH⁺).

Methyl-piperidin-4-yl-carbamic acid methyl ester hydrochloride

In analogy to the procedure described for intermediate 30C, 3-methoxymethyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester gave the title compound as white solid. MS: 173.0 (MH⁺).

Intermediate 40 (rac)-Piperidin-3-yl-carbamic acid methyl ester hydrochloride (rac)-3-Methoxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester

In analogy to the procedure described for intermediate 38A, (rac)-3-amino-1-BOC-piperidine gave the title compound as off-white gum. MS: 258.9 (MH⁺).

(rac)-Piperidin-3-yl-carbamic acid methyl ester hydrochloride

In analogy to the procedure described for intermediate 30C, (rac)-3-methoxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester gave the title compound as off-white solid. MS: 159.2 (MH⁺).

Intermediate 41 Ethyl-carbamic acid piperidin-4-yl ester hydrochloride 4-Ethylcarbamoyloxy-piperidine-1-carboxylic acid tert-butyl ester

A solution of 1.50 g (7.45 mmol) of N-BOC-4-hydroxypoperidine in 20 ml of DMF was treated at RT with 0.74 (7.45 mmol) of copper(I) chloride and 0.59 ml (7.45 mmol) of ethyl isocyanate. The reaction was stirred for 4 h at 0° C. and the partitioned between aqueous 10% NaCl and Et₂O (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na₂SO₄ evaporated and purified by flash silica gel column (n-heptane/EtOAc 4:1 to 2:1) to yield 1.66 g (82%) of the title compound as light yellow oil. MS: 273.1 (MH⁺).

Ethyl-carbamic acid piperidin-4-yl ester hydrochloride

In analogy to the procedure described for intermediate 30C, 4-ethylcarbamoyloxy-piperidine-1-carboxylic acid tert-butyl ester gave the title compound as white powder. MS: 173.0 (MH⁺).

Intermediate 42 4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-piperidine 4-(N′-Acetyl-hydrazinocarbonyl)-piperidine-1-carboxylic acid benzyl ester

A suspension of 0.80 g (3.04 mmol) of 1-[(benzyloxy)carbonyl]-4-piperidinecarboxylic acid and 0.25 g (3.34 mmol) in 28 ml CH₂Cl₂ of N-acethyl hydrazine was treated at 0° C. with 0.73 g (3.80 mmol) of EDCI. Over night, the suspension was naturally warmed to RT, poured on aqueous 10% KHSO₄ solution and extracted with CH₂Cl₂ (3×). The organic phases were washed with aqueous saturated NaHCO₃ and aqueous 10% NaCl, dried (Na₂SO₄) and evaporated to give 0.84 g (87%) of the title compound as white solid. MS: 320.2 (MH⁺).

4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-piperidine-1-carboxylic acid benzyl ester

A suspension of 2.00 g (6.26 mmol) of 4-(N′-acetyl-hydrazinocarbonyl)-piperidine-1-carboxylic acid benzyl ester in 30 ml acetonitril was treated at RT with 0.69 ml (7.51 mmol) of phosphoroxychloride. The suspension was stirred 1 h at RT and the refluxed for 2 h, evaporated, dissolved in CH₂Cl₂ and neutralized with aqueous saturated NaHCO₃ solution. The aqueous phase was extracted with CH₂Cl₂ (2×). The organic phase was dried (Na₂SO₄) and and evaporated to give after flash silica gel column (EtOAc) 1.69 g (89%) of the title compound as light yellow oil. MS: 302.1 (MH⁺).

4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-piperidine

A suspension of 100 mg (0.33 mmol) of 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-piperidine-1-carboxylic acid benzyl ester in 5 ml EtOAc and 10 mg Pd/C 10% was hydrogenated (1 atm) for 1 h. The reaction was filtered (Celite) and evaporated to give 55.4 mg (99%) of the title compound as white solid. MS: 167.9 (MH⁺).

Intermediate 43 4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidine hydrochloride 4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidine-1-carboxylic acid tert-butyl ester

A solution 1.30 g (17.49 mmol) of acetamide oxime in 55 ml THF was treated with 0.76 g (17.49 mmol) of NaH (55% in oil) and the corresponding suspension stirred for 45 min at RT. 3.00 g (11.66 mmol) of ethyl 1-tert-butoxycarbonylpiperidine-4-carboxylate dissolved in 15 ml of THF was added and heated at 65° C. for 2 h. The solution was cooled to RT, poured on aqueous saturated NH₄Cl solution and extracted with Et₂O (3×). The organic phases were washed with aqueous saturated NaHCO₃ and aqueous 10% KHSO₄, dried (Na₂SO₄) and evaporated to give 2.19 g (70%) of the title compound as orange liquid. MS: 268.2 (MH⁺).

4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidine hydrochloride

In analogy to the procedure described for intermediate 30C, 4-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidine-1-carboxylic acid tert-butyl ester gave the title compound as off-white solid. MS: 168.1 (MH⁺)).

Intermediate 44 (rac, cis)-2-Hydroxyrnethyl-piperidin-4-ol hydrochloride (rac, cis)-4-Hydroxy-piperidine-2-carboxylic acid methyl ester hydrochloride

A solution of 1.09 g (5.00 mmol) (1RS,5SR)-2-benzyl-6-oxa-2-aza-bicyclo[3.2.1]octan-7-one (Journal of Organic Chemistry (1996), 61(6), 2226-31) in 25 ml of MeOH was treated with a solution of HCl in dioxane (1.38 ml, 4 M in dioxane, 5.50 mmol) and 109 mg of Pd(OH)₂/C (20%) and was stirred over H₂-atmosphere for 2.5 h. After filtration, the solution was evaporated under reduced pressure and precipitated from CH₂Cl₂/Et₂O to yield 0.81 g (83%) of the title compound as an off-white powder, MS: 160.2 (MH⁺).

(rac, cis)-4-Hydroxy-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

A solution of 0.70 g (4.40 mmol) (rac, cis)-4-hydroxy-piperidine-2-carboxylic acid methyl ester hydrochloride and 1.01 g (4.62 mmol) di-tert-butyl-dicarbonate in 10 ml CH₂Cl₂ was slowly treated with 0.77 ml (5.50 mmol) Et₃N. The reaction was stirred for 30 min at RT, poured on ice cold aqueous 10% KHSO₄ solution and extracted with Et₂O (3×). The organic phases were washed with aqueous 10% KHSO₄ and aqueous 10% NaCl, dried (Na₂SO₄) and evaporated to give 1.09 g (96%) of the title compound as light yellow oil. MS: 259.9 (MH⁺).

(rac, cis)-4-(tert-Butyl-dimethyl-silanyloxy)-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

A solution of 1.00 g (3.88 mmol) (rac, cis)-4-hydroxy-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester and 0.87 g (12.79 mmol) imidazole in 2.5 ml DMF was cooled to 0° C. and treated with 0.64 g (7.7 mmol, 1.1 eq) TBDMSCl. After 30 min, the solution was stirred at RT for 1 h. Additional 0.12 g (0.78 mmol, 1.1 eq) TBDMSCl were added and stirred for additional 3 h. The solution was added to ice water and extracted with Et₂O (3×). The organic phases were washed with water and aqueous 10% NaCl, dried (Na₂SO₄) and evaporated to give after flash silica gel column (n-heptane/EtOAc 1:9 to 1:4) 1.04 g (72%) of the title compound as colorless oil. MS: 374.3 (MH⁺).

(rac, cis)-4-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester

4.46 ml (1.2 M in toluene, 5.35 mmol) of DIBALH was dropped to a dry ice cooled (−30° C.) solution of 1.00 g (2.68 mmol) (rac, cis)-4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in 15 ml of THF. The reaction was warmed up (0° C. for 1 h), continued for 1.5 h, cooled (−15° C.) and treated again with 0.45 ml (1.2 M in toluene, 0.54 mmol) of DIBALH. After 2 h at 0° C., the reaction was neutralized with aqueous 10% KHSO₄ solution. The mixture was extracted with ether (3×), the organic phases were washed with a aqueous 10% NaCl solution, dried (Na₂SO₄) and evaporated to give 0.98 g (quantitative) of the title compound as light yellow waxy solid. MS: 346.2 (MH⁺).

(rac, cis)-2-Hydroxymethyl-piperidin-4-ol hydrochloride

A solution of 0.16 g (0.45 mmol) of (rac, cis)-4-(tert-butyl-dimethyl-silanyloxy)-2-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester dissolved in 1 ml of MeOH was treated at 0° C. with a solution of HCl in dioxane (1.12 ml, 4 M in dioxane) and stirred for 30 min at 0° C. The reaction was then concentrated to dryness, re-evaporated with toluene and precipitated with CH₂Cl₂/Et₂O to give 0.05 g (68%) of the title product as white solid. MS: 132.3 (MH⁺)

Intermediate 45 (rac, cis)-2-Methoxymethyl-piperidin-4-ol hydrochloride (rac, cis)-4-(tert-Butyl-dimethyl-silanyloxy)-2-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester

In analogy to the procedure described for intermediate 31A, (rac, cis)-4-(tert-butyl-dimethyl-silanyloxy)-2-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (intermediate 44D) gave the title compound as colorless oil. MS: 360.3 (MH⁺).

(rac, cis)-2-Methoxymethyl-piperidin-4-ol hydrochloride

In analogy to the procedure described for intermediate 44E, (rac)-cis-4-(tert-butyl-dimethyl-silanyloxy)-2-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester gave after precipitation with MeOH/Et₂O the title compound as white solid. MS: 146.0 (MH⁺).

Intermediate 46 (rac, trans)-2-Hydroxymethyl-piperidin-4-ol hydrochloride (rac, cis)-1-Benzyl-4-hydroxy-piperidine-2-carboxylic acid methyl ester

A solution of 4.35 g (20.00 mmol) (1RS,5SR)-2-benzyl-6-oxa-2-aza-bicyclo[3.2.1]octan-7-one (Journal of Organic Chemistry (1996), 61(6), 2226-31) in 100 ml of MeOH was treated at 0° C. with a solution of HCl in dioxane (5.50 ml, 4 M in dioxane, 220 mmol) and was stirred for 24 h at RT. The solution was evaporated under reduced pressure, partitioned in water acidified with 0.1 N HCl/Et₂O and washed with Et₂O (2×). The aqueous phase was basified with aqueous saturated NaHCO₃ and extracted with Et₂O (3×). These organic phases were washed with 10% NaCl, dried over Na₂SO₄ and evaporated to give 4.25 g (85%) of the title compound as a viscous yellow oil, MS: 250.0 (MH⁺).

(rac, trans)-1-Benzyl-4-formyloxy-piperidine-2-carboxylic acid methyl ester

A solution of 1.84 ml (8.00 mmol) of di-tert-butyl azodicarboxylate in 3.1 ml of THF was slowly added (during 10 min, exothermic!) to a solution of 1.00 g (4.00 mmol) (rac, cis)-1-benzyl-4-hydroxy-piperidine-2-carboxylic acid methyl ester, 2.10 g (8.00 mmol) triphenylphosphine and 0.30 (8.00 mmol) formic acid in 11 ml THF. During the addition, the reaction was cooled to RT with a water bath. The resulting suspension was stirred at RT for 16 h, then added to diluted aqueous 10% KHSO₄ and washed with Et₂O (3×). The aqueous phase was basified with NaHCO₃ and extracted with Et₂O (3×). The organic phases were washed with aqueous 10% NaCl dried over Na₂SO₄ and evaporated to give 0.93 g of crude product. Flash silica gel column (n-heptane/EtOAc 95/5) gave 0.53 g (47%) of the title compound as light yellow oil. MS: 278.0 (MH⁺).

(rac, trans)-1-Benzyl-2-hydroxymethyl-piperidin-4-ol

7.51 ml (1.2 M in toluene, 9.01 mmol) of DIBALH was dropped to a dry ice cooled (−30° C.) solution of 0.50 g (1.80 mmol) (rac, trans)-1-benzyl-4-formyloxy-piperidine-2-carboxylic acid methyl ester in 9 ml of THF. The reaction was warmed up (0° C. for 1 h), and stirred for 1 h at this temperature, then added to diluted aqueous 10% KHSO₄ and washed with Et₂O (3×). The aqueous phase was basified with NaHCO₃, saturated with NaCl and extracted with EtOAc (3×). The organic phase was dried over Na₂SO₄ and evaporated to give 0.34 g (85%) of the title compound as off-white solid. MS: 222.0 (MH⁺).

(rac, trans)-2-Hydroxymethyl-piperidin-4-ol hydrochloride

In analogy to the procedure described for intermediate 35A, (rac, trans)-1-benzyl-2-hydroxymethyl-piperidin-4-ol gave after precipitation with CH₂Cl/₂Et₂O the title compound as white powder. MS: 132.3 (MH⁺).

Intermediate 47 (rac, cis)-4-Hydroxymethyl-piperidin-3-ol hydrochloride (rac, cis)-4-Hydroxymethyl-piperidin-3-ol hydrochloride

In analogy to the procedure described for intermediate 35A, (rac, cis)-1-benzyl-4-hydroxymethyl-piperidin-3-ol (Helvetica Chimica Acta, Volume 87, Number 10, 2629-2661) gave the title compound as light brown solid. MS: 132.3 (MH⁺).

Intermediate 48 (rac, trans)-4-Hydroxymethyl-piperidin-3-ol hydrochloride (rac, trans)-4-Hydroxymethyl-piperidin-3-ol hydrochloride

In analogy to the procedure described for intermediate 35A, (rac, trans)-1-benzyl-4-hydroxymethyl-piperidin-3-ol (Helvetica Chimica Acta, Volume 87, Number 10, 2629-2661) gave the title compound as orange solid. MS: 132.16 (MH⁺).

Intermediate 49 (rac, cis)-4-Methoxymethyl-piperidin-3-ol hydrochloride (rac, cis)-1-Benzyl-4-methoxymethyl-piperidin-3-ol, (rac, cis)-1-Benzyl-3-methoxy-piperidin-4-yl)-methanol and ((rac, cis)-1-Benzyl-3-methoxy-4-methoxymethyl-piperidine

A solution of 0.80 g (3.63 mmol) of (rac, cis)-1-benzyl-4-hydroxymethyl-piperidin-3-ol (Helvetica Chimica Acta, Volume 87, Number 10, 2629-2661) in 40 ml of THF was treated at 0° C. with 0.45 g (3.99 mmol) of potassium tert-butylate and after 10 min with slowly with 0.25 ml (3.99 mmol) of iodomethane in 20 ml of THF. Over night, the solution was naturally warmed to RT, partitioned between Et₂O/aqueous saturated NaHCO₃ and extracted again with Et₂O (2×). The organic phases were washed with aqueous saturated NaHCO₃, dried over Na₂SO₄ evaporated and gave after purification on a flash isolute NH₂-column (n-heptane/EtOAc 95:5 to 4:1) 0.33 g (39%) of (rac, cis)-1-benzyl-4-methoxymethyl-piperidin-3-ol as light yellow oil, MS: 236.1 (MH⁺), Rf=0.39 on silicagel with n-heptane/EtOAc 1:1;

0.17 g (20%) of (rac, cis)-1-benzyl-3-methoxy-piperidin-4-yl)-methanol as light yellow oil, MS: 236.1 (MH⁺), Rf=0.19 on silicagel with n-heptane/EtOAc 1:1;

and 0.09 g (10%) (rac, cis)-1-benzyl-3-methoxy-4-methoxymethyl-piperidine as light yellow oil, MS: 250.2 (MH⁺), Rf=0.02 on silicagel with n-heptane/EtOAc 1:1.

(rac, cis)-4-Methoxymethyl-piperidin-3-ol hydrochloride

A solution of 0.31 g (1.39 mmol) (rac, cis)-1-benzyl-4-methoxymethyl-piperidin-3-ol in 6 ml of EtOH was treated with a solution of 1.43 ml of aqueous 1 N HCl and 30 mg of Pd/C (10%) and was stirred over H₂-atmosphere for 2 day. After filtration, the solution was evaporated, suspended in acetonitrile and evaporated again under reduced pressure to yield 0.25 g (quantitative) of the title compound as a white solid. MS: 146.3 (MH⁺).

Intermediate 50 (rac, cis)-(3-Methoxy-piperidin-4-yl)-methanol hydrochloride (rac, cis)-(3-Methoxy-piperidin-4-yl)-methanol hydrochloride

In analogy to the procedure described for intermediate 49B, (rac, cis)-1-benzyl-3-methoxy-piperidin-4-yl)-methanol (intermediate 49A) gave the title compound as light yellow oil. MS: 146.3 (MH⁺).

Intermediate 51 (rac, cis)-3-Methoxy-4-methoxymethyl-piperidine hydrochloride (rac, cis)-3-Methoxy-4-methoxymethyl-piperidine hydrochloride

In analogy to the procedure described for intermediate 49B, (rac, cis)-1-benzyl-3-methoxy-piperidin-4-yl)-methanol (intermediate 49A) gave the title compound as light brown oil. MS: 160.2 (MH⁺).

Intermediate 52 (rac, cis)-4-Hydroxymethyl-4-methyl-piperidin-3-ol hydrochloride (rac)-1-Benzyl-4-methyl-3-oxo-piperidine-4-carboxylic acid ethyl ester

A milky solution of 7.75 g (69.02 mmol) of potassium tert-butylate in 125 ml of THF was cooled (0° C.) and treated portion wise with 10.44 g (34.00 mmol) of ethyl-N-benzyl-3-oxo-4-piperidin-carboxylate hydrochloride so the temperature did not rise over 5° C. After 1 h at RT, the reaction was cooled (0° C.) and ad treated slowly with 5.07 ml (35.70 mmol) of iodomethane in 4 ml of THF. After 4.5 h at RT, the reaction was cooled (0° C.) and neutralized with 40 ml of aqueous saturated NH₄Cl solution. The aqueous phase was extracted with Et₂O (3×). The organic phases were washed with aqueous saturated NaCl, dried over Na₂SO₄ and evaporated to give 4.97 g (53%) of the title compound as orange oil. MS: 276.1 (MH⁺).

(rac, cis)-1-Benzyl-4-hydroxymethyl-4-methyl-piperidin-3-ol and (rac, trans)-1-Benzyl-4-hydroxymethyl-4-methyl-piperidin-3-ol

24.33 ml (1.2 M in toluene, 29.20 mmol) of DIBALH was dropped to a dry ice cooled (−30° C.) solution of 2.01 g (7.30 mmol) (rac)-1-benzyl-4-methyl-3-oxo-piperidine-4-carboxylic acid ethyl ester in 37 ml of THF. Over night, the solution was naturally warmed to RT, cooled (0° C.) and treated again with 6.08 ml (1.2 M in toluene, 7.30 mmol) of DIBALH. After 4 h at RT, the reaction was neutralized with ice cooled aqueous 10% KHSO₄ solution. The mixture was extracted with ether (3×), the organic phases were washed with aqueous 10% KHSO₄ and aqueous 10% NaCl solution, dried (Na₂SO₄) and evaporated to give after flash silica gel column (CH₂Cl₂/MeOH 99:1 to 95:5) 0.28 g (16%) of (rac, cis)-1-benzyl-4-hydroxymethyl-4-methyl-piperidin-3-ol as a viscous orange oil, MS: 236.1 (MH⁺), 0.20 g (12%) of a cis/trans mixture of (rac)-1-benzyl-4-hydroxymethyl-4-methyl-piperidin-3-ol and 0.19 g (11%) (rac, trans)-1-benzyl-4-hydroxymethyl-4-methyl-piperidin-3-ol as a viscous orange oil. MS: 236.3 (MH⁺)

(rac, cis)-4-Hydroxymethyl-4-methyl-piperidin-3-ol hydrochloride

In analogy to the procedure described for intermediate 49B, hydrogenation of (rac, cis)-1-benzyl-4-hydroxymethyl-4-methyl-piperidin-3-ol (intermediate 52B) in MeOH gave after 2.5 days the title compound as light yellow solid. MS: 146.1 (MH⁺).

Intermediate 53 (rac, trans)-4-Hydroxymethyl-4-methyl-piperidin-3-ol hydrochloride (rac, trans)-4-Hydroxymethyl-4-methyl-piperidin-3-ol hydrochloride

In analogy to the procedure described for intermediate 35A, hydrogenation of (rac, trans)-1-benzyl-4-hydroxymethyl-4-methyl-piperidin-3-ol (intermediate 52B) in MeOH gave after 3 days the title compound as light yellow waxy solid. MS: 146.1 (MH⁺).

Intermediate 54 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-[1,4]diazepan-5-one 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-[1,4]diazepan-5-one

In analogy to the procedure described for intermediate 1A, (E)-3-chloro-4-fluorocinnamic acid and 2,3,6,7-tetrahydro-(1H)-1,4-diazepin-5(4H)-one gave the title compound as white solid. MS: 297.2 (MH⁺, 1Cl).

Intermediate 55 1-[(E)-3-(3,4-Difluoro-phenyl)-acryloyl]-[1,4]diazepan-5-one 1-[(E)-3-(3,4-Difluoro-phenyl)-acryloyl]-[1,4]diazepan-5-one

In analogy to the procedure described for intermediate 1A, (E)-4,4-difluorocinnamic acid and 2,3,6,7-tetrahydro-(1H)-1,4-diazepin-5(4H)-one gave the title compound as white solid.

MS: 281.2 (MH⁺).

Intermediate 56 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-((R)-2-oxiranyl-ethyl)-[1,4]diazepan-5-one 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-((R)-2-oxiranyl-ethyl)-[1,4]diazepan-5-one

In analogy to the procedure described for example 172A to 172C, 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 54) and methanesulfonic acid 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester gave the title compound as pink oil. MS: 367.0 (MH⁺, 1Cl).

Intermediate 57 1-[(E)-3-(4-Chloro-3-fluoro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one 1-[(E)-3-(4-Chloro-3-fluoro-phenyl)-acryloyl]-[1,4]diazepan-5-one

In analogy to the procedure described for intermediate 1A, (E)-4-chloro-3-fluorocinnamic acid and 2,3,6,7-tetrahydro-(1H)-1,4-diazepin-5(4H)-one gave the title compound as white solid. MS: 297.3 (MH⁺).

1-[(E)-3-(4-Chloro-3-fluoro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one

In analogy to the procedure described for example 9A and 9B, 1-[(E)-3-(4-chloro-3-fluoro-phenyl)-acryloyl]-[1,4]diazepan-5-one gave the title compound as light yellow solid. MS: 478.8 (MH⁺, 1Cl).

Intermediate 58 (rac)-1-[(E)-3-(3,4-Difluoro-phenyl)-acryloyl]-4-(2-oxiranyl-ethyl)-[1,4]diazepan-5-one (rac)-1-[(E)-3-(3,4-Difluoro-phenyl)-acryloyl]-4-(2-oxiranyl-ethyl)-[1,4]diazepan-5-one

In analogy to the procedure described for example 170A, 1-[(E)-3-(3,4-difluoro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 55) and (rac)-2-(2-bromo-ethyl)-oxirane (Journal of Organic Chemistry (1969), 34(12), 4060-5) gave the title compound as light yellow viscous oil. MS: 351.3 (MH⁺).

Intermediate 59 3-{4-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propionaldehyde 3-{4-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propionaldehyde

In analogy to the procedure described for intermediate 2A and 2B, 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 54) gave the title compound as colorless gum. MS: 353.2 (MH⁺, 1Cl).

Intermediate 60 3-{4-[(E)-3-(4-Chloro-3-fluoro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propionaldehyde 3-{4-[(E)-3-(4-Chloro-3-fluoro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propionaldehyde

In analogy to the procedure described for intermediate 2A and 2B, 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 57A) gave the title compound as white solid. MS: 353.1 (MH⁺, 1Cl).

Intermediate 61 5-Oxo-4-(3-oxo-propyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester 5-Oxo-4-(3-oxo-propyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester

In analogy to the procedure described for intermediate 2A and 2B, 5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester gave the title compound as colorless oil. MS: 215.3 (M⁺-tert-butyl).

Intermediate 62 (rac, cis)-2-Hydroxymethyl-piperidin-3-ol (rac)-3-Hydroxy-2-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester

A suspension of 5 g (31.00 mmol) of 2-hydroxymethyl-pyridin-3-ol hydrochlorid and 2.50 g 5% Rh/Alox in 100 ml AcOEt was stirred under hydrogen atmosphere 20 h at 25° C. and 8 bar. The suspension was filtered and evaporated to give an yellow oil. The crude product was treated with 8.78 g (40.00 mmol) BOC₂O and 12 ml (93.00 mmol) Hunig's base in 30 ml DMF under ice cooling for 25 h. An extraction (water/brine/AcOEt) and two crystallizations (AcOEt, MeCN/CH₂Cl₂) gave 1.77 g (25%) of the title compound as a white solid. MS: 232.0 (MH⁺).

(rac, cis)-2-Hydroxymethyl-piperidin-3-ol hydrochlorid

0.80 g (3.46 mmol) of (rac)-3-hydroxy-2-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester in 10 ml dioxane was treated with 4M HCl/dioxane for 18 h at RT to give the title compound as white solid 0.15 g (100%). MS: 132.2 (MH⁺).

Intermediate 63 (rac, cis)-6-Methoxymethyl-piperidin-3-ol 5-Benzyloxy-4-chloro-2-methoxymethyl-pyridine

A solution of 9.30 g (172 mmol) of sodium methylate in 132 ml methanol was added drop wise to a solution of 5-benzyloxy-4-chloro-2-chloromethyl-pyridine (Australian Journal of chemistry, 1977, 30, 649) in 130 ml DMSO. The suspension was heated at 100° C. for 6 h, poured on ice, extracted with four portions of CH₃Cl. The organic phases were dried (Na₂SO₄), evaporated and distilled (Kp 0.2 mm Hg, 150-152° C.) to give 12.80 g (91%) of the title compound. MS: 264.0 (MH⁺).

(rac, cis)-6-Methoxymethyl-piperidin-3-ol

A suspension of 1.00 g (3.79 mmol) of 5-benzyloxy-4-chloro-2-methoxymethyl-pyridine and 0.20 g 5% Rh/Alox in 25 ml methanol was stirred under hydrogen atmosphere 20 h at 50° C. and 8 bar. The suspension was filtered, evaporated and purified by silica gel column (AcOEt) to give 0.55 g (99%, 84% cis- and 16% trans-isomer) of the titled compound as a light yellow oil

MS: 146.3 (MH⁺).

Intermediate 64 (rac, cis)-2-Methoxymethyl-6-methyl-piperidin-3-ol [3-(4-Methoxy-benzyloxy)-6-methyl-pyridin-2-yl]-methanol

1.39 g (10 mmol) of the commercial 3-hydroxy-6-methyl-2-pyridinemethanol in 15 ml DMF was cooled (0° C.), treated with 0.52 g (13.00 mmol) of NaH (55% in oil) and after 30 min, with 1.35 mL (10.00 mmol) p-methoxybenzylchlorid. The suspension was stirred 1 h at 0° C. and 2 h at RT. The reaction mixture was diluted with CH₂Cl₂ and washed with 1M NaOH and brine. The organic layers were dried over magnesium sulfate, evaporated, purified by silica gel column (AcOEt) and crystallized (AcOEt/n-n-heptane) to give 1.55 g (60%) of the title compound as a white solid. MS: 260.0 (MH⁺).

3-(4-Methoxy-benzyloxy)-2-methoxymethyl-6-methyl-pyridine

1.55 g (6.00 mmol) of [3-(4-Methoxy-benzyloxy)-6-methyl-pyridin-2-yl]-methanol in cold 10 ml THF (0° C.) was treated 30 min with 0.41 g (10.30 mmol) of NaH (55% in oil), then 0.43 ml (6.90 mmol) of iodomethane was added and the yellow suspension stirred 1 h. An extraction (water/CH₂Cl₂) and a chromatography (silica gel, AcOEt/n-n-heptane) delivered 1.41 g (86%) of the title compound as a yellow oil. MS: 274.3 (MH⁺).

(rac, cis)-2-Methoxymethyl-6-methyl-piperidin-3-ol

3-(4-Methoxy-benzyloxy)-2-methoxymethyl-6-methyl-pyridine was hydrogenated using the method described in intermediate 63B to give the title compound as a white solid. MS: 160.2 (MH⁺).

Intermediate 65 (rac, cis)-6-Hydroxymethyl-piperidin-3-ol (rac)-5-Hydroxy-2-methyl-piperidine-1-carboxylic acid tert-butyl ester and (rac, cis)-5-Hydroxy-2-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester

1.50 g (9.28 mmol) of 6-Hydroxymethyl-pyridin-3-ol hydrochlorid was hydrogenated under the conditions described in intermediate 63B. The crude product was dissolved in 5 ml DMF, 5.60 ml (32.00 mmol) of Hunig's base and 3.56 g (16.00 mmol) of BOC₂O were added and the yellow solution was stirred 18 h at RT. Evaporation, extraction (AcOEt/water/brine) and chromatography (silica gel, AcOEt/MeOH) gave 0.35 g (15%) (rac)-5-hydroxy-2-methyl-piperidine-1-carboxylic acid tert-butyl ester; MS: 216.4 (MH⁺)

and 0.24 g (10%) (rac, cis)-5-hydroxy-2-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester of the title compound as a light yellow oil. MS: 232.1 (MH⁺).

(rac, cis)-6-Hydroxymethyl-piperidin-3-ol hydrochlorid

In analogy to intermediate 62B, (rac, cis)-5-hydroxy-2-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester gave the title compound was obtained as a light brown solid. MS: 132.0 (MH⁺).

Intermediate 66 (rac)-6-Methyl-piperidin-3-ol

In analogy to intermediate 62B, 5-hydroxy-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (intermediate 65A) gave title compound as a light brown solid. MS: 116.3 (MH⁺).

Intermediate 67 (rac)-5-Methoxy-piperidin-2-yl)-methanol

In analogy to the procedure described for intermediate 63B, (5-methoxy-pyridin-2-yl)-methanol gave the title compound as a light yellow oil. MS: 146.3 (MH⁺).

Intermediate 68 4-Methoxy-6-methoxymethyl-piperidin-3-ol; hydrochloride

4-Methoxy-6-methoxymethyl-pyridin-3-ol [prepared from 5-benzyloxy-4-chloro-2-methoxymethyl-pyridine (intermediate 63A) by reaction with 1) NaOMe, 2) MCPBA, 3) PdC/H₂] was hydrogenated in analogy to intermediate 63B to give the title compound as a white solid MS: 176.2 (MH⁺).

Intermediate 69 N-(2R,4S,5R)-(5-Methoxy-2-methoxymethyl-piperidin-4-yl)-acetamide and N-(2S,4R,5S)-(5-Methoxy-2-methoxymethyl-piperidin-4-yl)-acetamide

0.60 g (2.93 mmol) of 5-Methoxy-2-methoxymethyl-pyridin-4-ylamine (prepared by treatment of the 5-methoxy-2-methoxymethyl-pyran-4-one with aqueous 25% ammonia at 100° C.) in 10 mL CH₂Cl₂ was treated at 0° C. with 0.26 mL (3.65 mmol) acetyl chloride and 1.25 ml (7.30 ml) Hunig's base. After 20 min, the suspension was diluted with CH₂Cl₂ and washed with aqueous 10% Na₂CO₃ and brine. The organic layers were dried over magnesium sulfate and evaporated to give 0.71 g of the title compound as a yellow gum. The crude product was hydrogenated in analogy to intermediate 63B. A chromatography (silica gel, AcOEt/MeOH) and crystallization (AcOEt/n-n-heptane) gave 0.09 g (11%) of the title compound as a white solid. MS: 217.2 (MH⁺).

Intermediate 70 (rac, trans)-6-Methyl-piperidin-3-ol

g (9.16 mmol) of 6-Methyl-pyridin-3-ol was hydrogenated under the conditions described in intermediate 63B, then chromatographed (silica gel, AcOEt/MeOH) to give 161 mg (15%) of the title compound as a white solid. MS: 116.2 (MH⁺).

Intermediate 71 (rac)-2,6-Bis-methoxymethyl-piperidin-3-ol

2.00 g (8.15 mmol) of (5-benzyloxy-6-hydroxymethyl-pyridin-2-yl)-methanol (prepared from 2,6-bis-hydroxymethyl-pyridin-3-ol by treatment with benzylbromide, K₂CO₃ in MeCN, WO 2006100305) was reacted in analogy to intermediate 64B and intermediate 64C to give 0.83 g (74%) of the title compound as a yellow oil. MS: 190.4 (MH⁺).

Intermediate 72 (rac)-2-(6-Hydroxymethyl-piperidin-3-yloxy)-acetamide 2-(6-Hydroxymethyl-pyridin-3-yloxy)-acetamide

1.25 g (6.35 mmol) of (6-Hydroxymethyl-pyridin-3-yloxy)-acetic acid methyl ester (prepared from 6-methyl-pyridin-3-ol by reaction with: 1) Chloro-acetic acid methyl ester, 2) m-Cl-perbenzoic acid and 3) trifluoroacetic acid anhydride) was treated with 31 ml 7M NH₃ in MeOH for 2.5 h at RT. The suspension was evaporated to give 1.19 g (100%) of the title compound as a white solid. MS: 183.3 (MH⁺).

(rac)-2-(6-Hydroxymethyl-piperidin-3-yloxy)-acetamide

2-(6-Hydroxymethyl-pyridin-3-yloxy)-acetamide was hydrogenated as described in intermediate 63B, to give the title compound as a yellow gum. MS: 189.4 (MH⁺).

Intermediate 73 (rac)-2-Methoxymethyl-piperidin-3-ol

In analogy to the procedure described for intermediate 64, 2-hydroxymethyl-pyridin-3-ol gave the title compound as yellow oil. MS: 146.4 (MH⁺).

Intermediate 74 (rac, trans)-6-Methoxymethyl-piperidin-3-ol (rac, cis)-5-hydroxy-2-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester and (rac, trans)-5-hydroxy-2-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester

In analogy to the procedure described for intermediate 65A, crude (rac)-6-methoxymethyl-piperidin-3-ol (intermediate 63B) gave after separation by silica gel column (AcOEt) 34% of the (rac, cis)-5-hydroxy-2-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester and 6% of the (rac, trans)-5-hydroxy-2-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester as a light yellow liquid. MS: 246.3 (MH⁺).

(rac, trans)-6-Methoxymethyl-piperidin-3-ol hydrochlorid

In analogy to the procedure described for intermediate 62B, (rac, trans)-5-hydroxy-2-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester gave the title compound as a white solid. MS: 146.4 (MH⁺).

Intermediate 75 (rac, cis)-5-Methyl-piperidin-3-ol hydrochloride (rac, cis)-3-Hydroxy-5-methyl-piperidine-1-carboxylic acid tert-butyl ester and (rac, cis)-3-Hydroxy-5-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester

A solution of 1.20 g (9.59 mmol) of 5-hydroxymethyl-pyridin-3-ol (Jensen, Henrik Helligso; Lyngbye, Laila; Jensen, Astrid; Bols, Mikael. Chemistry—A European Journal (2002), 8(5), 1218-1226) in 1.3 ml of aqueous 25% HCl and 10 ml of MeOH was hydrogenated with 0.60 g 10% Pd/C at 50 bar and 120° C. for 20 h. Filtration and reaction with new catalyst with the same conditions gave crude product which was reacted with di-tert-butyl-dicarbonate in analogy to intermediate 44B. Purification by silica gel column (n-n-heptane/iso-propanol 95:5 to 1:1) gave 0.50 g (27%) of (rac, cis)-3-hydroxy-5-methyl-piperidine-1-carboxylic acid tert-butyl ester as light yellow oil, MS: 216.2 (MH⁺)

and 0.15 g (8%) of rac-3-hydroxy-5-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester as light yellow oil. MS: 232.0 (MH⁺).

(rac, cis)-5-Methyl-piperidin-3-ol hydrochloride

In analogy to the procedure described for intermediate 62B, (rac, cis)-3-hydroxy-5-methyl-piperidine-1-carboxylic acid tert-butyl ester gave the title compound as a white solid. MS: 116.3 (MH⁺).

Intermediate 76 (rac)-5-Hydroxymethyl-piperidin-3-ol hydrochloride (rac)-5-Hydroxymethyl-piperidin-3-ol hydrochloride

In analogy to the procedure described for intermediate 62B, rac-3-hydroxy-5-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester gave the title compound as orange gum. MS: 132.2 (MH⁺).

Intermediate 77 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-3-methyl-[1,4]diazepan-5-one (rac)-1-Benzyl-3-methyl-[1,4]diazepan-5-one

Sodium azide (1.58 g, 24.4 mmol) was added portionwise over 6 h to a solution of 1-benzyl-3-methylpiperidin-4-one (5.00 g, 24.4 mmol) at 0° C., then the reaction mixture was allowed to reach room temperature over 16 h. The reaction mixture was then poured upon ice/40% aq. sodium hydroxide solution/ethyl acetate, the organic layer was washed with brine, dried (MgSO₄), and evaporated. Recrystallization in n-heptane/ethyl acetate 2:1 (60 ml) produced the title compound (2.59 g, 49%). White solid, MS: 219.3 (MH⁺).

(rac)-3-Methyl-[1,4]diazepan-5-one

A mixture of 1-benzyl-3-methyl-[1,4]diazepan-5-one (1.88 g, 8.62 mmol) and palladium (10% on activated charcoal, 188 mg) in ethanol (50 ml) was stirred at room temperature under a hydrogen atmosphere (3 bar). After 18 h, the catalyst was removed by filtration and the filtrate evaporated to afford the title compound (1.12 g, 99%). White solid, MS: m/e=128 (M⁺).

(rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-3-methyl-[1,4]diazepan-5-one

In analogy to the procedure described in intermediate 1A, (E)-3,4-dichlorocinnamic acid and 3-methyl-[1,4]diazepan-5-one gave the title compound as a white solid. MS: 327.2 (MH⁺).

Intermediate 78 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-methyl-[1,4]diazepan-5-one (rac)-7-Methyl-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester

2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (WO2002072584; 454 mg, 2.03 mmol) was added to a solution of 3-benzyloxycarbonylamino-butyric acid ethyl ester (450 mg, 1.69 mmol) and potassium tert-butylate (228 mg, 2.03 mmol). The reaction mixture was stirred for 72 h at room temperature and heated at 50° C. for another 24 h. After cooling, the reaction mixture was partitioned between 10% aq. citric acid solution and ethyl acetate, the organic layer was washed with brine, dried (MgSO₄), and evaporated. The residue was taken up in dichloromethane (10 ml), treated with trifluoroacetic acid (2.5 ml), stirred at room temperature for 45 min, then evaporated. The residue was dissolved in methanol (10 ml), then potassium carbonate (3.08 g, 22.3 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After evaporation, the residue was partitioned between ethyl acetate and 1 M aq. sodium hydroxide solution. The organic layer was washed with brine, dried (MgSO₄), and evaporated. Chromatography (SiO₂; CH₂Cl₂/MeOH/NH₄OH 95:5:0.25) produced the title compound (205 mg, 46%). Colorless gum, MS: 263.2 (MH⁺).

(rac)-7-Methyl-[1,4]diazepan-5-one

A mixture of 7-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester (201 mg, 0.77 mmol) and palladium (10% on activated charcoal, 80 mg) in ethanol (2 ml) was stirred at room temperature under a hydrogen atmosphere (3 bar). After 20 h, the catalyst was removed by filtration and the filtrate evaporated to afford the title compound (81 mg, 82%). White solid,

MS: 128 (M⁺).

(rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-methyl-[1,4]diazepan-5-one

-   -   -(7-Azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium         hexafluorophosphate (343 mg, 0.90 mmol) was added to a solution         of 3,4-dichlorocinnamic acid (130 mg, 0.60 mmol),         7-methyl-[1,4]diazepan-5-one (77 mg, 0.60 mmol), and         4-methylmorpholine (304 mg, 3.01 mmol) in N,N-dimethylformamide         (1 ml). The reaction mixture was stirred for 3 h at room         temperature, then partitioned between n-heptane/ethyl acetate         1:1 and water. The organic layer was washed with brine, dried         (MgSO₄), and evaporated. Chromatography (SiO₂;     -   CH₂Cl₂MeOH/NH₄OH 95:5:0.25) produced the title compound (193 mg         98%). Colorless gum, MS: 327.1 (MH⁺).

Intermediate 79 (R)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-2-methyl-[1,4]diazepan-5-one (R)-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester

In analogy to the procedure described in intermediate 78A, 3-benzyloxycarbonylamino-propanoic acid methyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (Bioorg. Med. Chem. Lett. 2006, 16, 1207) gave the title compound. Colorless gum, MS: m/e=263.1 (MH⁺).

(R)-2-Methyl-[1,4]diazepan-5-one

In analogy to the procedure described in intermediate 78B, (R)-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester gave the title compound. Colorless gum, MS: m/e=128 (M⁺).

(R)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-2-methyl-[1,4]diazepan-5-one

In analogy to the procedure described in intermediate 78C, (E)-3,4-dichlorocinnamic acid and (R)-2-methyl-[1,4]diazepan-5-one gave the title compound as a colorless gum, MS: m/e=327.3 (MH⁺).

Intermediate 80 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-6-methyl-[1,4]diazepan-5-one (rac)-6-Methyl-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester

Sodium hydride (60% dispersion in mineral oil, 275 mg, 6.88 mmol) was added at room temperature to a solution of tert-butyl N-(2-aminoethyl)carbamate (1.00 g, 6.24 mmol), then after 30 min ethyl methacrylate (712 mg, 6.24 mmol) was added. The reaction mixture was stirred at room temperature over 16 h, then partitioned between ethyl acetate/n-heptane 1:1 and water. The organic layer was washed with brine, dried (MgSO₄), and evaporated. Chromatography (SiO2; ethyl acetate, then CH₂Cl₂/MeOH/NH₄OH 95:5:0.25) produced the title compound (51 mg, 4%). White solid, MS: m/e=229.4 (MH⁺).

(rac)-6-Methyl-[1,4]diazepan-5-one hydrochloride

6-Methyl-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (42 mg, 0.18 mmol) was suspended in hydrogen chloride solution (4 M in 1,4-dioxane, 0.5 ml) and stirred at room temperature for 4 h, then volatile material was removed by distillation, to afford the title compound (29 mg, 96%). Colorless gum, MS: 129.1 ([M−Cl]⁺).

(rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-6-methyl-[1,4]diazepan-5-one

In analogy to the procedure described in intermediate 78C, (E)-3,4-dichlorocinnamic acid and 6-methyl-[1,4]diazepan-5-one hydrochloride gave the title compound as a colorless gum, MS: 327.1 (MH⁺).

Intermediate 81 (rac)-6-Aza-spiro[2.5]octan-4-ol hydrochloride A] (rac)-6-Aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester

To a solution of Et₂Zn (37.5 ml, 1.1M solution in toluene, 0.04 mmol) in DCE (80 ml) at 0° C. was added chloroiodomethane (5.99 ml, 0.08 mmol) under Ar. This mixture was stirred for 15 minutes before a solution of 3-hydroxy-4-methylene-piperidine-1-carboxylic acid tert-butyl ester (J. Org. Chem. 2001, 66, 2487) (4.19 g, 0.02 mmol) in DCE (10 ml) was added, after which time the reaction was stirred for 0.5 h at 0° C. and then allowed to reach room temperature, stirring for a further 1 h. The reaction was then quenched by addition of saturated NH₄Cl, separated, and the organic dried (Na₂SO₄) and concentrated. Purfication by flash column chromatography (EtOAc:n-heptane 2:8-1:1) afforded the title product (2.4 g, 54%) as a crystalline solid. MS: 228.2 (MH⁺).

(rac)-6-Aza-spiro[2.5]octan-4-ol hydrochloride

Intermediate 81A (0.52 g, 2 mmol) was dissolved in 10 ml of HCl in dioxane (4M), stirred for ten minutes. The reaction was then concentrated to afford the title product (0.38 g, quant.) as a white powder. MS: 128.1 (MH⁺).

Intermediate 82 (+)-6-Aza-spiro[2.5]octan-4-ol hydrochloride

The title compound was prepared by chiral separation of Intermediate 81A on a Chiralpak AD column (Isopropanol:n-heptane 5:95) and subsequent analogous deprotection with HCl in dioxane. MS: 128.1 (MH⁺).

Intermediate 83 (−)-6-Aza-spiro[2.5]octan-4-ol hydrochloride

The title compound was prepared by chiral separation of Intermediate 81A on a Chiralpak AD column (Isopropanol:n-heptane 5:95) and subsequent analogous deprotection with HCl in dioxane. MS: 128.1 (MH⁺).

Intermediate 84 (rac)-3-Hydroxy-4,4-dimethyl-piperidine hydrochloride (rac)-3-Hydroxy-4,4-dimethyl-piperidine-1-carboxylic acid tert-butyl ester

Intermediate 81A (0.43 g, 1.9 mmol) was dissolved in AcOH (7 ml) with platinum oxide (0.4 g, 1.9 mmol) and stirred under hydrogen atmosphere (balloon) for 2 d. The reaction was then filtered through Hyflo and concentrated to afford the title product (0.41 g, 94%) as oil. MS: 230.2 (MH⁺).

(rac)-3-Hydroxy-4,4-dimethyl-piperidine hydrochloride

Intermediate 84A was deprotected with HCl in dioxane to afford the title product as a white powder. MS: 130.1 (MH⁺).

Intermediate 85 (+, cis)-4-Methyl-piperidin-3-ol hydrochloride (rac, trans)-3-Hydroxy-4-methyl-piperidine-1-carboxylic acid tert-butyl ester

(rac, trans)-1-Benzyl-4-methyl-piperidin-3-ol (Tet. Lett. 2000, 5817) (13.0 g, 63 mmol) was dissolved in MeOH with Pd(OH)₂/C (4 g) and stirred under a hydrogen atmosphere (balloon) for 16 h after which time Boc₂O (13.8 g, 63 mmol) was added, the reaction stirred for 1 h, filtered through Hyflo and concentrated to afford the title product (13.3 g, 98%) as a crystalline solid. MS: 216.2 (MH⁺).

(rac, cis)-4-Methyl-3-(4-nitro-benzoyloxy)-piperidine-1-carboxylic acid tert-butyl ester

Intermediate 85A (6.0 g, 28 mmol) was dissolved in THF (40 ml) with PPh₃ (8.9 g, 34 mmol), 4-nitrobenzoic acid (5.7 g, 34 mmol) and cooled to 0° C. before dropwise addition of diisopropyldiazadicarboxylate (6.9 g, 34 mmol). The ice bath was removed and the reaction allowed coming to room temperature, stirring for 16 h. The reaction was then directly absorbed onto silica gel and purified by flash column chromatography (EtOAc:n-heptane 2:8) to afford the title product (4.0 g, 40%) as a white solid. MS: 365.2 (MH⁺).

(rac, cis)-3-Hydroxy-4-methyl-piperidine-1-carboxylic acid tert-butyl ester

Intermediate 85B (5.0 g, 14 mmol) was dissolved in MeOH (70 ml) and NaOH (4.5 ml, 6N in water, 27 mmol) was added. The reaction was stirred for 1 h after which time the solvent removed under vacuum, the residue portioned between water and CH₂Cl₂ and the organic collected, dried (Na₂SO₄) and concentrated toafford the title product (2.6 g, 87%) as a crystalline solid. MS: 216.1 (MH⁺).

(+, cis)-3-hydroxy-4-methyl-piperidine-1-carboxylic acid tert-butyl ester

Intermediate 85C was separated on a Chiralpak AD column (Isopropanol:n-heptane 5:95) to afford the title compound. MS: 216.1 (MH⁺).

(+, cis)-4-Methyl-piperidin-3-ol hydrochloride

Intermediate 85D was deprotected with HCl in dioxane to afford the title compounds as a white powder. MS: 116.2 (MH⁺).

Intermediate 86 (−, cis)-4-Methyl-piperidin-3-ol hydrochloride

The title compound was prepared in analogy to Intermediate 85D and subsequently deprotected with HCl in dioxane to afford the title product as a white powder. MS: 116.2 (MH⁺).

Intermediate 87 (rac, trans)-2-Methyl-piperidin-3-ol hydrochloride (rac, trans)-3-Hydroxy-2-methyl-piperidine-1-carboxylic acid tert-butyl ester

Hydroxy-2- methylpyridine (2.0 g, 18 mmol) was dissolved in MeOH (40 ml) with 5% Rh on alumina (0.27 g) and heated to 30° C. at 90 bar of hydrdogen atmosphere for 22 h. The reaction was then filtered through Hyflo, Boc₂O (4.0 g, 18 mmol) added and the reaction stirred for 1 h before removing the solvent under vacuum. The residue was redissolved in CH₂Cl₂, washed with 10% citric acid solution, dried (Na₂SO₄) and concentrated. Purification by flash column chromatography (EtOAc:n-heptane 3:7-1:1) afforded the title product (0.7 g, 18%) of the title product as a light yellow liquid. MS: 216.1 (MH⁺). A small quantity of (rac, cis)-3-hydroxy-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.06 g, 2%) was also obtained from the column. MS: 216.1 (MH⁺).

(rac, trans)-2-Methyl-piperidin-3-ol hydrochloride

Intermediate 87A (0.7 g, 3 mmol) was deprotected using HCl in dioxane affording the title product (0.45 g, 91%) as a white powder. MS: 116.1 (MH⁺).

Intermediate 88 (rac, cis)-2-Methyl-piperidin-3-ol hydrochloride

The byproduct (rac, cis)-3-hydroxy-2-methyl-piperidine-1-carboxylic acid tert-butyl ester from the reaction to make intermediate 87A was deprotected with HCl in dioxane to afford the title compound. MS: 116.1 (MH⁺).

Intermediate 89 (rac, trans)-4-Fluoro-piperidin-3-ol hydrochloride (rac, trans)-4-Fluoro-piperidin-3-ol-1-carboxylic acid tert-butyl ester

(rac)-7-Oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (Heter. 1994, 39, 163) (2.0 g, 10 mmol) was dissolved in a mixture of DCE (1.5 ml) and trisHF.Et₃N (1.6 g, 10 mmol) and heated to 80° C. for 12 h after which time the reaction was diluted with CH₂Cl₂, washed with sat. NaHCO₃, then sat. NH₄Cl, dried (Na₂SO₄) and concentrated. Purification by flash column chromatography (EtOAc:n-heptane 3:7) afforded the title compound (1.5 g, 66%) as a yellow liquid. MS: 220.1 (MH⁺). Also obtained was the regioisomer (rac, trans)-3-fluoro-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.26 g, 12%) as a yellow oil. MS: 220.1 (MH⁺).

(rac, trans)-4-Fluoro-piperidin-3-ol hydrochloride

Intermediate 89A (0.5 g, 2 mmol) was deprotected with HCl in dioxane affording the title product (0.34 g, 95%) as a white powder. MS: 120.1 (MH⁺).

Intermediate 90 (rac, trans)-3-Fluoro-piperidin-4-ol hydrochloride

The byproduct (rac, trans)-3-fluoro-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester ester from the reaction to make intermediate 89A was deprotected with HCl in dioxane to afford the title compound. MS: 120.1 (MH⁺).

Intermediate 91 (rac)-4-Methyl-piperidin-3-ol hydrochloride 3-Hydroxy-4-methyl-piperidine-1-carboxylic acid tert-butyl ester

Hydroxy-4-methylpyridine (0.98 g, 9 mmol) was dissolved in a AcOH (50 ml) and Pt₂O (0.10 g) added. The mixture was heated to 100° C. under 100 bar of hydrogen pressure for 20 h. The reaction was then filtered through Hyflo and concentrated. The residue was dissolved in CH₂Cl₂ (30 ml) and Et₃N (2.75 ml, 20 mmol) and Boc₂O (2.2 g, 10 mmol) added and the mixture stirred for 1 h. The reaction was then washed with 10% citric acid solution, dried (Na₂SO₄) and concentrated. Purification by flash column chromatography (EtOAc:n-heptane 3:7) afforded the title product (0.63 g, 33%), a 3:1 mixture of diasteriomers (cis:trans) as a colourless oil. MS: 216.1 (MH⁺).

(rac)-4-Methyl-piperidin-3-ol hydrochloride

Intermediate 91A was deprotected with HCl in dioxane to afford the title product as a white powder. MS: 116.1 (MH⁺).

Intermediate 92 4-[3-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one dihydrochloride 4-[3-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester

5-Oxo-4-(3-oxo-propyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (intermediate 61) (0.19 g, 0.7 mmol) was reacted with (−)-6-Aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 83) (0.12 g, 0.7 mmol) in DCE:EtOH (1:1, 6 ml), AcOH (0.18 ml) and pyridine-borane complex (0.18 ml, 8M in pyridine, 1.4 mmol) for 20 minutes. The reaction was then concentrated, redissolved in CH₂Cl₂ and washed with sat. NaHCO₃, dried (Na₂SO₄) and concentrated. The residue was purified by flash column chromatography (CH₂Cl₂:MeOH 8:2) to afford the title product (0.25 g, 91%) as a gum. MS: 382.4 (MH⁺).

4-[3-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one dihydrochloride

Intermediate 92A was deprotected with HCl in dioxane to afford the title product as a white powder. MS: 282.3 (MH⁺).

Intermediate 93 (rac, cis)-3-Fluoro-piperidin-4-ol hydrochloride 3-Fluoro-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester

Fluoro-4- oxo-piperidine-1-carboxylic acid tert-butyl ester (Chem. Europ. J. 2005, 5, 1579) (1.0 g, 5 mmol) was dissolved in MeOH (5 ml), cooled to 0° C. and sodium borohydride (0.2 g, 5 mmol) was added portionwise. The reaction was allowed to reach room temperature and stirred overnight after which time the solvent was removed under vacuum, the residue redissolved in CH₂Cl₂, washed with water, dried (Na2_(S)O₄) and concentrated. The product was purified by flash column chromatography (EtOAc:n-heptane 3:7-1:1) to afford the title compound (0.67 g, 67%) as a white solid. ¹H NMR (400 MHz, DMSO) δ 1.19-1.68 (11H, m), 2.80-3.0 (1H, m), 3.06-3.17 (1H, m), 3.59-3.70 (2H, m), 3.90-3.97 (1H, m), 4.55 (1H, dt, J 52, 4 Hz).

(rac, cis)-3-Fluoro-piperidin-4-ol hydrochloride

Intermediate 93A was deprotected with HCl in dioxane to afford the title compound as a white powder. MS: 120.1 (MH⁺).

Intermediate 94 (rac)-3-Methyl-piperidin-4-ol (rac)-1-Benzyl-3-methyl-piperidin-4-ol

Benzyl-3- methyl-piperidin-4-one (2.0 g, 10 mmol) was dissolved in MeOH (10 ml), cooled to 0° C. and sodium borohydride (0.2 g, 5 mmol) was added portionwise. The reaction was allowed to reach room temperature and stirred overnight after which time the solvent was removed under vacuum, the residue redissolved in CH₂Cl₂, washed with water, dried (Na2SO₄) and concentrated to afford the title compound (2.1 g, quant), a 3:1 mixture of diasteriomers (trans:cis) as gum. MS: 206.2 (MH⁺).

(rac)-3-Methyl-piperidin-4-ol

Intermediate 94A (0.93 g) was dissolved in EtOH (10 ml) and Pd(OH)₂/C (0.2 g) and cyclohexen (2 ml) added. The reaction was heated to reflux for 16 h after which time it was filtered through Hyflo and concentrated, affording the title product (0.52 g, quant) a brown oil.

MS: 116.1 (MH⁺).

Intermediate 95 (rac, trans)-3-Methyl-piperidin-4-ol hydrochloride (rac, trans)-4-Hydroxy-3-methyl-piperidine-1-carboxylic acid tert-butyl ester

Benzyl-5-methyl-1,2,3,6-tetrahydro-pyridine (Tet. Lett. 1998, 39, 5417) (7.7 g, 41 mmol) was dissolved in THF (100 ml) and sodium borohydride (2.6 g, 69 mmol) added. The mixture was cooled to 0° C. and borontrifluoride etherate (6.2 ml, 49 mmol) added, the reaction allowed to reach room temperature and subsequently stirred for 1 h. The reaction was recooled to 0° C., a small quantity of water added to quench any remaining borane, and then a suspension of Oxone (42.6 g, 69 mmol) in water (100 ml) was added and the reaction again allowed to reach room temperature (1 h). The reaction was filtered, extacted with EtOAc, the aqeous phase made basic by addition of solid NaOH, and then reextracted with CH₂Cl₂, dried (Na₂SO₄) and concentrated. The crude residue (5.2 g) was redissolved in MeOH, Pd(OH)₂/C added and the reaction stirred under an atmosphere of hydrogen (balloon) for 16 h after which time Boc₂O (5.5 g, 25 mmol) was added, the reaction stirred for 1 h, and then filtered through Hyflo and concentrated. Purification by flash column chromatography (EtOAc:n-heptane 4:6) afforded the title product (2.1 g, 39%) as a colourless gum. MS: 216.2 (MH⁺).

(rac, trans)-3-Methyl-piperidin-4-ol hydrochloride

Intermediate 95A was deprotected with HCl in dioxane to afford the title product as a white powder. MS: 116.2 (MH⁺).

Intermediate 96 (rac, cis)-3-Methyl-piperidin-4-ol hydrochloride (rac, cis)-3-Methyl-4-(4-nitro-benzoyloxy)-piperidine-1-carboxylic acid tert-butyl ester

Intermediate 95A (0.6 g, 3 mmol) was converted to the 4-nitrobenzoic ester analogously to Intermediate 85B affording the titled product (0.9 g, 90%) as a white solid. MS: 365.2 (MH⁺).

(rac, cis)-4-Hydroxy-3-methyl-piperidine-1-carboxylic acid tert-butyl ester

Intermediate 96A (0.86 g, 2 mmol) was saponified analogously to intermediate 85C affording the title product (0.5 g, 98%) as a colourless oil. MS: 216.4 (MH⁺).

(rac, cis)-3-Methyl-piperidin-4-ol hydrochloride

Intermediate 96B was deprotected with HCl in dioxane to afford the title product as a white powder. MS: 116.1 (MH⁺).

Intermediate 97 (rac)-3,3-Dimethyl-piperidin-4-ol (rac)-1-Benzyl-3,3-dimethyl-piperidin-4-ol

Benzyl-3,3-dimethyl-piperidin-4-one (WO 01/00577 A2) (5.0 g, 23 mmol) was dissolved in MeOH (25 ml), cooled to 0° C. and sodium borohydride (1.0 g, 25 mmol) was added portionwise. The reaction was allowed to reach room temperature and stirred overnight after which time the solvent was removed under vacuum, the residue redissolved in CH₂Cl₂, washed with water, dried (Na₂SO₄) and concentrated to afford the title compound (4.9 g, 97%). MS: 220.4 (MH⁺).

(rac)-3,3-Dimethyl-piperidin-4-ol

Intermediate 97A (4.9 g) was dissolved in EtOH (50 ml) and Pd(OH)₂/C (0.3 g) and cyclohexene (6 ml) added. The reaction was heated to reflux for 16 h after which time it was filtered through Hyflo and concentrated, affording the title product (0.5 g, quant) a white crystalline solid. MS: 130.1 (MH⁺).

Intermediate 98 (rac)-5-Aza-spiro[2.5]octan-8-ol 8-Oxo-5-aza-spiro[2.5]octane-5-carboxylic acid tert-butyl ester

4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 5 mmol) was dissolved in tBuOH (10 ml) with tBuOK (1.1 g, 10 mmol) and stirred for 15 minutes before portionwise addition of (2-chloro-ethyl)-dimethyl-sulfonium iodide (Tet. Lett. 1984, 25, 5501) (1.1 g, 5 mmol) over 1 h. The reaction was stirred for 16 h after which time it was partioned between water and CH₂Cl₂, the organic collected, dried (Na₂SO₄) and concentrated. Flash column chromatography (EtOAc:n-heptane 1:9-3:7) afforded the titled product (0.2 g, 19%) as a colourless oil. MS: 130.1 (MH⁺).

(rac)-8-Hydroxy-5-aza-spiro[2.5]octane-5-carboxylic acid tert-butyl ester

Intermediate 98A (0.2 g, 1 mmol) was dissolved in MeOH (5 ml) and sodium borohydride (0.04 g, 1 mmol) added. The reaction was stirred for 1 h, concentrated, partitioned between CH₂Cl₂ and water, the organic collected, dried (Na₂SO₄) and concentrated. Flash column chromatography (EtOAc:n-heptane 3:7-1:1) afforded the titled prouduct (0.15 g, 68%) as colourless gum. MS: 228.1 (MH⁺).

(rac)-5-Aza-spiro[2.5]octan-8-ol

Intermediate 98B was deprotected with HCl in dioxane to afford the titled product as a white poweder. MS: 128.1 (MH⁺).

Intermediate 99 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one

In analogy to the procedure described for example 9A and 9B, 1-[(E)-3-(3-chloro-4-fluoro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 54) gave the title compound as yellow foam. MS: 478.9 (MH⁺).

Intermediate 100 (rac, trans)-4-Methyl-piperidin-3-ol hydrochloride

The title compound was prepared from intermediate 85B, (rac, trans)-3-Hydroxy-4-methyl-piperidine-1-carboxylic acid tert-butyl ester, by deprotection with HCl in dioxane.

MS:116.2 (MH⁺).

Intermediate 101 (rac)-3-Methyl-piperidin-3-ol hydrochloride

The title compound was prepared in analogy to intermediate 16. MS:116.2 (MH⁺).

Intermediate 102 Oxa-4,9-diaza-spiro[5.5]undecan-3-one

The title compound was prepared as described in J. Med. Chem. 1983, 26, 6, 855.

Example 1 1-[(E)-3-(3-Chloro-phenyl)-acryloyl]-4-(2-pyrrolidin-1-yl-ethyl)-[1,4]diazepan-5-one 1-[(E)-3-(3-Chloro-phenyl)-acryloyl]-4-(2-pyrrolidin-1-yl-ethyl)-[1,4]diazepan-5-one

In analogy to the procedure described in intermediate 4A, 1-[(E)-3-(3-chloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 3A]) and 1-(2-chloro-ethyl)-pyrrolidine gave the title compound as off-white powder. MS: 376.5 (MH⁺, Cl).

Example 2 4-[2-(4-Acetyl-piperazin-1-yl)-ethyl]-1-[(E)-3-(3-chloro-phenyl)-acryloyl]-[1,4]diazepan-5-one 4-[2-(4-Acetyl-piperazin-1-yl)-ethyl]-1-[(E)-3-(3-chloro-phenyl)-acryloyl]-[1,4]diazepan-5-one

In analogy to the procedure described in intermediate 4A, 1-[(E)-3-(3-chloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 3A]) and 1-[4-(2-chloro-ethyl)-piperazin-1-yl]-ethanone gave the title compound as off-white foam. MS: 433.2 (MH⁺, Cl).

Example 3 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(2-piperidin-1-yl-ethyl)-[1,4]diazepan-5-one 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(2-piperidin-1-yl-ethyl)-[1,4]diazepan-5-one

In analogy to the procedure described in intermediate 4A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A) and 1-(2-chloro-ethyl)-piperidine gave the title compound as white solid. MS: 424.1 (MH⁺, 2Cl).

Example 4 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one

In analogy to the procedure described in intermediate 4A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A) and 1-(3-chloro-propyl)-piperidine gave the title compound as light yellow solid. MS: 438.1 (MH⁺, 2Cl).

Example 5 1-[(E)-3-(3-Chloro-phenyl)-acryloyl]-4-(2-morpholin-4-yl-ethyl)-[1,4]diazepan-5-one {4-[(E)-3-(3-Chloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-acetic acid ethyl ester

A solution of 4.33 g (15.53 mmol) of 1-[(E)-3-(3-chloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 3A) in 80 ml of DMF was treated at 0° C. with 0.75 g (17.09 mmol) of NaH (55% in oil) in two portions and after 30 min with 1.89 ml (17.09 mmol) of bromo-acetic acid ethyl ester in 1 ml of DMF. The reaction was stirred for 5 h at RT, cooled (0° C.) and treated again with 0.20 g (4.66 mmol) of NaH (55% in oil) and after 20 min with 0.34 ml (3.11 mmol) of bromo-acetic acid ethyl ester. The reaction was warmed up to RT over night, cooled and neutralized with cold aqueous 10% KHSO₄ and extracted with Et₂O (3×). The organic phases were washed with aqueous saturated NaHCO₃, aqueous 10% NaCl, dried over Na₂SO₄ evaporated and purified by flash silica gel column (EtOAc/n-heptane 1:1 to 9:1) to yield 2.92 g (52%) of the title compound as light yellow viscous oil. MS: 365.0 (MH⁺, Cl).

1-[(E)-3-(3-Chloro-phenyl)-acryloyl]-4-(2-hydroxy-ethyl)-[1,4]diazepan-5-one

A solution of 2.16 g (5.91 mmol) of {4-[(E)-3-(3-chloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-acetic acid ethyl ester in 30 ml of ethanol was treated at 0° C. with 0.45 g (11.81 mmol) of sodium borohydride in 30 ml of ethanol during 20 min. The reaction was stirred for 21 h at RT, cooled (0° C.) and treated again with 0.45 g (11.81 mmol) of sodium borohydride. After 22 h at RT the reaction neutralized with cold aqueous 10% KHSO₄ and extracted with EtOAc (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na₂SO₄ evaporated and purified by flash silica gel column (EtOAc and then EtOAc/EtOH 1 to 7.5%) to yield 1.50 g (79%) of the title compound as light white foam. MS: 323.1 (MH⁺, Cl).

4-(2-Chloro-ethyl)-1-[(E)-3-(3-chloro-phenyl)-acryloyl]-[1,4]diazepan-5-one

To an ice-cooled solution of 2.13 g (3.50 mmol) of 1-[(E)-3-(3-chloro-phenyl)-acryloyl]-4-(2-hydroxy-ethyl)-[1,4]diazepan-5-one and 0.73 ml (5.25 mmol) of Et₃N in 35 ml of dichloromethane were added 0.29 ml (3.68 mmol) of methanesulfonyl chloride under stirring within 5 min keeping the temperatue at 0° C. The reaction was stirred at room temperature for 1 h 45 min. Water was added and after 5 min, the reaction was then partitioned between ether and aqueous saturated NaHCO₃. The water phase was extracted again with ether (2×), the organic phases were washed with aqueous 10% NaCl, dried (Na₂SO₄) and concentrated to yield 1.22 g (87%) of the title compound as yellow viscous oil. MS: 341.0 (MH⁺, 2Cl).

1-[(E)-3-(3-Chloro-phenyl)-acryloyl]-4-(2-morpholin-4-yl-ethyl)-[1,4]diazepan-5-one

A solution of 0.085 g (0.25 mmol) of 4-(2-chloro-ethyl)-1-[(E)-3-(3-chloro-phenyl)-acryloyl]-[1,4]diazepan-5-one in 1.3 ml of DMA was treated with 0.04 ml (0.50 mmol) of morpholine and stirred for 8 h at RT, a crystal of NaI was added and stirring was continued for 40 h. The reaction was extracted with aqueous saturated NaHCO₃/EtOAc (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na₂SO₄), concentrated and evaporated. Purification by catridges, Si-Amine, 70 ml, 20 g (EtOAc) gave 0.008 g (8%) of the title compound as off-white viscous oil. MS: 392.0 (MH⁺, Cl).

Example 6 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(3-morpholin-4-yl-propyl)-[1,4]diazepan-5-one 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-[1,4]diazepan-5-one

In analogy to the procedure described in example 5A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) and 2-(3-bromo-propoxy)-tetrahydro-pyran gave the title compound as white solid. MS: 455.3 (MH⁺, 2Cl).

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(3-hydroxy-propyl)-[1,4]diazepan-5-one

A solution of 1.30 g (2.85 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-[1,4]diazepan-5-one in 6 ml of methanol was treated with 0.22 g (0.86 mmol) of pyridinium toluene-4-sulfonate and stirred at 55° C. for 30 min. The reaction was cooled and extracted with aqueous 10% KHSO₄/Et₂O (3×). The organic phases were washed with aqueous saturated NaHCO₃, aqueous 10% NaCl, dried (Na₂SO₄) and evaporated to give after crystallization (Et₂O) 0.98 g (92%) of the title compound as white solid.

MS: 371.0 (MH⁺, 2Cl).

Methanesulfonic acid 3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propyl ester

In analogy to the procedure described in example 5C, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(3-hydroxy-propyl)-[1,4]diazepan-5-one and methanesulfonyl chloride gave the crude title compound as white foam and as a mixture of mainly mesylate and some chloride.

MS: 448.2 (M⁺, 2Cl).

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(3-iodo-propyl)-[1,4]diazepan-5-one

A solution of 0.50 g (1.11 mmol) of crude methanesulfonic acid 3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propyl ester in 20 ml of 2-butanone was treated with 0.33 g (2.23 mmol) of sodium iodide and stirred at 95° C. for 30 min. The reaction was cooled, evaporated, suspended in 60 ml dichloromethane/Et₂O (1:3), filtered and the organic solvent discarded. The residue was then washed again with dichloromethane to give after evaporation 0.27 g (51%) of the title compound as white solid. MS: 481.0 (MH⁺, 2Cl).

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(3-morpholin-4-yl-propyl)-[1,4]diazepan-5-one

In analogy to the procedure described in example 5D, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(3-iodo-propyl)-[1,4]diazepan-5-one and morpholine (with no additional sodium iodide) gave after flash silica gel column purification (CH₂Cl₂/EtOAc 99:1 to 96:4) the title compound as a light yellow viscous oil. MS: 440.2 (MH⁺, 2Cl).

Example 7 1-[(E)-3-(3,4-Difluoro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one 1-[(E)-3-(3,4-Difluoro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one

In analogy to the procedure described in intermediate 1A, (E)-3,4-difluorocinnamic acid and 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4B, suspended in CH₂Cl₂ with 4 equivalent of Et₃N) gave after purification on catridges, Si-Amine, 70 ml, 20 g (EtOAc) the title compound as a white powder. MS: 406.2 (MH⁺).

Example 8 4-(3-Piperidin-1-yl-propyl)-1-[(E)-3-(3-trifluoromethyl-phenyl)-acryloyl]-[1,4]diazepan-5-one 4-(3-Piperidin-1-yl-propyl)-1-[(E)-3-(3-trifluoromethyl-phenyl)-acryloyl]-[1,4]diazepan-5-one

In analogy to the procedure described in intermediate 1A, (E)-3-(trifluoromethyl)cinnamic acid and 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4B, suspended in CH₂Cl₂ with 4 equivalent of Et₃N) gave after purification on catridges, Si-Amine, 70 mL, 20 g (EtOAc) the title compound as a light yellow viscous oil. MS: 438.4 (MH⁺).

Example 9 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(4-piperidin-1-yl-butyl)-[1,4]diazepan-5-one 4-(4-Chloro-butyl)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one

In analogy to the procedure described in example 5A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) and 1-chloro-4-iodobutane gave the title compound as orange solid. MS: 403.2 (MH⁺, 3Cl).

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(4-iodo-butvl)-[1,4]diazepan-5-one

In analogy to the procedure described in example 6D, 4-(4-chloro-butyl)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one and sodium iodide were stirred at 90° C. for 26 h to give the title compound as orange foam. MS: 495.0 (MH⁺, 2Cl).

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(4-piperidin-1-yl-butyl)-[1,4]diazepan-5-one

In analogy to the procedure described in example 5D, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one and piperidine (with no additional sodium iodide) gave the title compound as white powder. MS: 452.2 (MH⁺, 2Cl).

Example 10 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-{4-[methyl-(tetrahydro-pyran-4-yl)-amino]-butyl}-[1,4]diazepan-5-one 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-{4-[methyl-(tetrahydro-pyran-4-yl)-amino]-butyl}-[1,4]diazepan-5-one

A solution of 0.100 g (0.20 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one (example 9B) in 3.1 ml of DMA was treated with free methyl-(tetrahydro-pyran-4-yl)-amine in 1 ml of toluene [0.035 g (0.22 mmol) methyl-(tetrahydro-pyran-4-yl)-amine hydrochloride were dissolved in 0.8 ml of 0.5 N NaOH was extracted with toluene (2 ml). The organic phase was dried over Na₂SO₄] and stirred for 22 h at RT, 0.06 ml (0.40 mmol) of Et₃N was added and stirring was continued for 18 h at 50° C. Again methyl-(tetrahydro-pyran-4-yl)-amine in 1 ml of CH₂Cl₂ [0.035 g (0.22 mmol) methyl-(tetrahydro-pyran-4-yl)-amine hydrochloridewere dissolved in 0.5 ml aqueous 10% NaCl solution/0.4 ml of 1 N NaOH was extracted with CH₂Cl₂ (1 ml). The organic phase was dried over Na₂SO₄] was added and heated for 9 h at 50° C. The reaction was extracted with aqueous saturated NaHCO₃/Et₂O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na₂SO₄), concentrated and evaporated. Purification by catridges, Si-Amine, 70 ml, 20 g (n-heptane/EtOAc 1:4 to 1:9) gave 0.004 g (4%) of the title compound as a light yellow semisolid. MS: 482.3 (MH⁺, 2Cl).

Example 11 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one

A suspension of 0.099 g (0.32 mmol) 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4B) and 0.077 g (0.38 mmol) of (E)-3-chloro-4-fluorocinnamic acid in 3 ml of CH₂Cl₂ was treated with 0.09 ml (0.64 mmol) of Et₃N at RT, cooled (0° C.) and treated with a 0.085 g (0.41 mmol) of N,N′-dicyclohexylcarbodiimide. The reaction was warmed up over night to RT, then partitioned between EtOAc (×3)/saturated NaHCO₃. The organic phases were washed with aqueous 10% NaCl, dried over Na₂SO₄ and evaporated to give after purification on catridges, Si-Amine, 70 ml, 20 g (EtOAc/n-heptane 9:1) 0.075 g (64%) of the title compound as a white solid. MS: 422.1 (MH⁺, Cl).

Example 12 1-[(E)-3-(5,6-Dichloro-pyridin-3-yl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one (E)-3-(5,6-Dichloro-pyridin-3-yl)-acrylic acid methyl ester

To a solution of (5,6-Dichloro-pyridin-3-yl)-methanol (1.8 g, 10 mmol) in CH₂Cl₂ (20 ml) was added manganese dioxide (4.4 g, 50 mmol). The reaction was stirred for 16 h after which time it was filtered through a pad of Hyflo and a fresh portion of manganese dioxide (1.8 g, 20 mmol) added and the reaction stirred for a further 4 h. The manganese dioxide was removed by filtration through Hyflo and the reaction concentrated affording crude 5,6-dichloro-pyridine-3-carbaldehyde (1.4 g, 81%). This was then dissolved in toluene (20 ml) and (methoxycarbonylmethylene)triphenylphosphorane (4.1 g, 12 mmol) added and the mixture heated to reflux for 1 h after which time the mixture was diluted with CH₂Cl₂, silica gel added and the mixture concentrated to dryness. The absorbed product was then purified by flash column chromatography (EtOAc:Heptane 1:1) furnishing the title compound (1.5 g, 81%) as a white solid.

MS: 232.0 (MH⁺, 2Cl).

(E)-3-(5,6-Dichloro-pyridin-3-yl)-acrylic acid

(E)-3-(5,6-Dichloro-pyridin-3-yl)-acrylic acid methyl ester (1.54 g, 7 mmol) was suspended in MeOH (20 ml) and aqueous sodium hydroxide (1.1 ml, 6M, 7 mmol) added. The mixture was heated to reflux for 20 min after which time the reaction was concentrated, the residue taken up in water and the pH adjusted to 1 by addition of 1M HCl. The product could then be isolated by filtration affording the title compound (1.11 g, 77%) as a white solid. MS: 216.0 (M−H⁻2Cl).

E)-3-(5,6-Dichloro-pyridin-3-yl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one

To a suspension of (E)-3-(5,6-Dichloro-pyridin-3-yl)-acrylic acid (26 mg, 0.12 mmol), 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4) (24 mg, 0.1 mmol), O-(7-azabenotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) in DMF (1 ml) was added Et₃N(21 ul, 0.15 mmol) and the mixture shaken fro 1 h. The reaction was then directly purified by preparative HPLC affording the title product (14 mg, 32%) as a white powder. MS: 439.4 (MH⁺, 2Cl).

Example 13 1-[(E)-3-(4-Chloro-3-fluoro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one 1-[(E)-3-(4-Chloro-3-fluoro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one

In analogy to the procedure described in intermediate 1A, 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4B) and (E)-4-chloro-3-fluorocinnamic acid gave after work up with EtOAc (×3)/saturated NaHCO₃ and precipitation (n-pentane) the title compound as off-white solid. MS: 422.2 (MH⁺, Cl).

Examples 14-26 General Procedure for Examples 14-26

A solution CDI (0.016 g, 0.1 mmol) in DMF (0.5 ml) was added to the appropriate cinnamic acid (0.1 mmol) and the solution shaken for 1 h after which time a solution of 4-(2-pyrrolidin-1-yl-ethyl)-[1,4]di-azepan-5-one-dihydrochoride (intermediate 5) ( 0.027 g, 0.1 mmol), Et₃N (28 ul, 0.2 mmol) in DMF (0.5 ml) was added and the shaking continued for 16 h. The reactions were then directly purified by preparative HPLC.

TABLE 1 Example MS: No. Compound Name Cinnamic Acid (MH⁺) 14 4-(2-Pyrrolidin-1-yl-ethyl)-1-[(E)-3- 4-Trifluoromethylcinnamic 410.5 (4-trifluoromethyl-phenyl)-acryloyl]- acid [1,4]diazepan-5-one 15 4-(2-Pyrrolidin-1-yl-ethyl)-1-[(E)-3- 4-Methoxycinnamic acid 372.5 (4-methoxy-phenyl)-acryloyl]- [1,4]diazepan-5-one 16 4-(2-Pyrrolidin-1-yl-ethyl)-1-[(E)-3- 2,4-Dichlorocinnamic acid 410.5 (2,4-dichloro-phenyl)-acryloyl]- [1,4]diazepan-5-one 17 1-[(E)-3-(4-Benzyloxy-phenyl)- 4-Benzyloxycinnamic acid 448.6 acryloyl]-4-(2-pyrrolidin-1-yl-ethyl)- [1,4]diazepan-5-one 18 1-(E)-(3-Benzo[1,3]dioxol-5-yl- 3,4- 386.5 acryloyl)-4-(2-pyrrolidin-1-yl-ethyl)- Methylenedioxycinnamic [1,4]diazepan-5-one acid 19 4-(2-Pyrrolidin-1-yl-ethyl)-1-[(E)-3- 2,4-Difluorocinnamic acid 378.5 (2,4-difluoro-phenyl)-acryloyl]- [1,4]diazepan-5-one 20 1-[(E)-3-(3,5-Difluoro-phenyl)- 3,5-Difluorocinnamic acid 378.5 acryloyl]-4-(2-pyrrolidin-1-yl-ethyl)- [1,4]diazepan-5-one 21 4-(2-Pyrrolidin-1-yl-ethyl)-1-[(E)-3- Cinnamic acid 342.5 phenyl-acryloyl]-[1,4]diazepan-5-one 22 4-(2-Pyrrolidin-1-yl-ethyl)-1-[(E)-3- 2-Methoxycinnamic acid 372.5 (2-methoxy-phenyl)-acryloyl]- [1,4]diazepan-5-one 23 4-(2-Pyrrolidin-1-yl-ethyl)-1-[(E)-3- 4-Fluorocinnamic acid 360.5 (4-fluoro-phenyl)-acryloyl]- [1,4]diazepan-5-one 24 4-(2-Pyrrolidin-1-yl-ethyl)-1-[(E)-3- 3-Fluorocinnamic acid 360.5 (3-fluoro-phenyl)-acryloyl]- [1,4]diazepan-5-one 25 1-(E)-(3-Naphthalen-2-yl-acryloyl)-4- 2-Napthyacrylic acid 392.5 (2-pyrrolidin-1-yl-ethyl)- [1,4]diazepan-5-one 26 4-(2-Pyrrolidin-1-yl-ethyl)-1-[(E)-3- 4-Chlorocinnamic acid 376.2 (4-chloro-phenyl)-acryloyl]- [1,4]diazepan-5-one

Examples 27-34 General Procedure for Examples 27-34

A solution of {4-[(E)-3-(3-chloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-acetaldehyde (intermediate 3) (0.031 g, 0.1 mmol) in DCE (0.5 ml) was added to the appropriate amine (0.1 mmol) followed by a freshly prepared solution of pyridine-borane complex (25 ul, 8M in pyridine, 0.2 mmol) and acetic acid (25 ul) in EtOH (0.5 ml). The reaction was then shaken overnight, concentrated and the residue purified by preparative HPLC.

TABLE 2 Example MS: No. Compound Name Amine (MH⁺) 27 1-[(E)-3-(3-Chloro-phenyl)- 6-Fluoro-3-piperidin-4-yl-1H- 522.8 acryloyl]-4-{3-[4-(6-fluoro-1H- indole (intermediate 6) indol-3-yl)-piperidin-1-yl]-ethyl}- [1,4]diazepan-5-one 28 1-[(E)-3-(3-chloro-phenyl)- 1-Piperidin-4-yl-imidazolidin-2- 473.8 acryloyl]-4-{3-[4-(2-oxo- one (intermediate 7) imidazolidin-1-yl)-piperidin-1- yl]-ethyl}-[1,4]diazepan-5-one 29 1-[(E)-3-(3-Chloro-phenyl)- 4-(5-Methyl-4H-[1,2,4]triazol- 470.8 acryloyl]-4-{3-[4-(5-methyl-1H- 3-yl)-piperidine hydrochloride [1,2,4]triazol-3-yl)-piperidin-1- (intermediate 8) yl]-ethyl}-[1,4]diazepan-5-one 30 4-[2-(4-Benzyl-piperidin-1-yl)- 4-Benzylpiperidine 479.8 ethyl]-1-[(E)-3-(3-chloro- phenyl)-acryloyl]-[1,4]diazepan- 5-one 31 1-[(E)-3-(3-Chloro-phenyl)- 4-Hydroxy-4-phenyl-piperidine 481.8 acryloyl]-4-[3-(4-hydroxy-4- phenyl-piperidin-1-yl)-propyl]- [1,4]diazepan-5-one 32 1-[(E)-3-Chloro-phenyl-acryloyl]- 4-Phenylpiperidine 465.8 4-{2-[4-phenyl-piperidin-1-yl]- ethyl}-[1,4]diazepan-5-one 33 1-[(E)-3-(3-Chloro-phenyl)- 4-(4-Fluoro-phenyl)-piperidine 483.8 acryloyl]-4-[3-(4-(4-fluoro- phenyl)-piperidin-1-yl)-ethyl]- [1,4]diazepan-5-one 34 1-[(E)-3-(3-Chloro-phenyl)- 4-(3-Chloro-phenyl)-piperidine 499.8 acryloyl]-4-{2-[4-(3-chloro- phenyl)-piperidin-1-yl]-ethyl}- [1,4]diazepan-5-one

Examples 35-92 General Procedure for Examples 35-92

A solution of 3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propionaldehyde (intermediate 2) (0.037 g, 0.1 mmol) in DCE (0.5 ml) was added to the appropriate amine (0.1 mmol) followed by a freshly prepared solution of pyridine-borane complex (25 ul, 8M in pyridine, 0.2 mmol) and acetic acid (25 ul) in EtOH (0.5 ml). The reaction was then shaken overnight, concentrated and the residue purified by preparative HPLC.

TABLE 3 Example MS: No. Compound Name Amine (MH⁺) 35 4-[3-(4-Cyclopropanecarbonyl- Cyclopropyl-piperazin-1-yl- 507.2 piperazin-1-yl)-propyl]-1-[(E)-3-(3,4- methanone dichloro-phenyl)-acryloyl]- [1,4]diazepan-5-one 36 4-[3-(Cyclopentyl-amino)-propyl]-1- Cyclopentylamine 438.2 [(E)-3-(3,4-dichloro-phenyl)- acryloyl]-[1,4]diazepan-5-one 37 4-[-3-(Cyclopentyl-methyl-amino)- Cyclopentyl-methyl-amine 452.2 propyl]-1-[(E)-3-(3,4-dichloro- phenyl)-acryloyl]-[1,4]diazepan-5-one 38 (+/−)-4-[3-(Bicyclo[2.2.1]hept-2- (+/−)-endo-2-Norbonylamine 464.2 ylamino)-propyl]-1-[(E)-3-(3,4- hydrochloride dichloro-phenyl)-acryloyl]-[1,4] diazepan-5-one 39 4-[3-(Cyclohexyl-methyl-amino)- Cylcohexyl-methyl-amine 466.2 propyl]-1-[(E)-3-(3,4-dichloro- phenyl)-acryloyl]-[1,4] diazepan-5- one 40 1-[(E)-3-(3,4-Dichloro-phenyl)- Thiomorpholine-1,1-dioxide 488.1 acryloyl]-4-[3-(1,1-dioxo- thiomorpholin-4-yl)-propyl]- [1,4]diazepan-5-one 41 1-[(E)-3-(3,4-Dichloro-phenyl)- (2-Methoxy-ethyl)-methyl- 442.2 acryloyl]-4-{3-[(2-methoxy-ethyl)- amine methyl-amino]-propyl}- [1,4]diazepan-5-one 42 1-[(E)-3-(3,4-Dichloro-phenyl)- (2-Hydroxy-ethyl)-methyl- 428.2 acryloyl]-4-{3-[(2-hydroxy-ethyl)- amine methyl-amino]-propyl}- [1,4]diazepan-5-one 43 4-{3-[Bis-(2-hydroxy-ethyl)-amino]- 2-(2-Hydroxy-ethylamino)- 458.2 propyl}-1-[(E)-3-(3,4-dichloro- ethanol phenyl)-acryloyl]-[1,4]diazepan-5-one 44 (+/−)-N-[1-(E)-(3-{4-[3-(3,4- (+/−)-N-Pyrrolidin-3-yl- 481.2 Dichloro-phenyl)-acryloyl]-7-oxo- acetamide [1,4] diazepan-1-yl}-propyl)- pyrrolidin-3-yl]-acetamide 45 1-[(E)-3-(3,4-Dichloro-phenyl)- 4-Phenyl-piperidine 514.2 acryloyl]-4-[3-(4-phenyl-piperidin-1- yl)-propyl]-[1,4]diazepan-5-one 46 1-[(E)-3-(3,4-Dichloro-phenyl)- Pyrollidine 424.2 acryloyl]-4-(3-pyrrolidin-1-yl- propyl)-[1,4]diazepan-5-one 47 (S)-1-[(E)-3-(3,4-Dichloro-phenyl)- (S)-Prolinol 454.2 acryloyl]-4-[3-(2-hydroxymethyl- pyrrolidin-1-yl)-propyl]- [1,4]diazepan-5-one 48 8-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)- 1,3,8-Triaza- 522.2 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- Spiro[4.5]decane-2,4-dione propyl)-1,3,8-triaza-spiro[4.5]decane- (intermediate 11) 2,4-dione 49 4-[(E)-3-(4-Benzyl-4-hydroxy- 4-Benzyl-piperidin-4-ol 544.2 piperidin-1-yl)-propyl]-1-[(E)-3-(3,4- dichloro-phenyl)-acryloyl]- [1,4]diazepan-5-one 50 1-[(E)-3-(3,4-Dichloro-phenyl)- 4-Methyl-piperidine 452.2 acryloyl]-4-[3-(4-methyl-piperidin-1- yl)-propyl]-[1,4]diazepan-5-one 51 1-[(E)-3-(3,4-Dichloro-phenyl)- Thiomorpholine 456.1 acryloyl]-4-(3-thiomorpholin-4-yl- propyl)-[1,4]diazepan-5-one 52 (+/−)-1-[(E)-3-(3,4-Dichloro-phenyl)- (1,4)-dioxan-2-yl- 484.2 acryloyl]-4-[3-([1,4]dioxan-2- methylamine ylmethyl-methyl-amino)-propyl]- [1,4]diazepan-5-one 53 1-[(E)-3-(3,4-Dichloro-phenyl)- 4-Hydroxy-4-pyrid-4- 531.2 acryloyl]-4-[3-(4-hydroxy-3,4,5,6- yl(piperidine) tetrahydro-2H-[4,4′]bipyridinyl-1-yl)- propyl]-[1,4]diazepan-5-one 54 cis/trans-1-[(E)-3-(3,4-Dichloro- cis/trans-Methyl-(4-methyl- 480.3 phenyl)-acryloyl]-4-{3-[methyl-(4- cyclohexyl)-amine methyl-cyclohexyl)-amino]-propyl}- [1,4]diazepan-5-one 55 1-[(E)-3-(3,4-Dichloro-phenyl)- 4,4-Difluororpiperidine 474.2 acryloyl]-4-[3-(4,4-difluoro-piperidin- 1-yl)-propyl]-[1,4]diazepan-5-one 56 1-[(E)-3-(3,4-Dichloro-phenyl)- Piperidin-4-yl- 522.2 acryloyl]-4-{3-[4-(2-oxo- imidazolidin-2- imidazolidin-1-yl)-piperidin-1-yl]- one propyl}-[1,4]diazepan-5-one (intermediate 7) 57 1-[(E)-3-(3,4-Dichloro-phenyl)- 4-(1H-Pyrazol-3-yl)- 504.2 acryloyl]-4-{3-[4-(1H-pyrazol-3-yl)- piperidine piperidin-1-yl]-propyl}- (intermediate 12) [1,4]diazepan-5-one 58 1-[(E)-3-(3,4-Dichloro-phenyl)- 4-(5-Methyl-4H- 519.2 acryloyl]-4-{3-[4-(5-methyl-1H- [1,2,4]triazol-3-yl)-piperidine [1,2,4]triazol-3-yl)-piperidin-1-yl]- hydrochloride propyl}-[1,4]diazepan-5-one (intermediate 8) 59 1-[(E)-3-(3,4-Dichloro-phenyl)- 4-Phenyl-piperidin-4-ol 530.5 acryloyl]-4-[3-(4-hydroxy-4-phenyl- piperidin-1-yl)-propyl]- [1,4]diazepan-5-one 60 1-(-3-{4-[(E)-3-(3,4-Dichloro- 4-Phenyl-piperidine-4- 539.5 phenyl)-acryloyl]-7-oxo- carbonitrile [1,4]diazepan-1-yl}-propyl)-4-phenyl- piperidine-4-carbonitrile 61 1-[(E)-3-(3,4-Dichloro-phenyl)- 4-Piperidin-4-yl-morpholine 523.5 acryloyl]-4-[3-(4-morpholin-4-yl- piperidin-1-yl)-propyl]- [1,4]diazepan-5-one 62 (+/−)-1-[(E)-3-(3,4-Dichloro-phenyl)- (+/−)-2-Methylpiperidine 452.4 acryloyl]-4-[3-(2-methyl-piperidin-1- yl)-propyl]-[1,4]diazepan-5-one 63 1-[(E)-3-(3,4-Dichloro-phenyl)- Tetrahydro-pyran-4-ylamine 454.5 acryloyl]-4-[3-(tetrahydro-pyran-4- ylamino)-propyl]-[1,4]diazepan-5- one 64 cis/trans-1-[(E)-3-(3,4-Dichloro- cis/trans-2- 466.4 phenyl)-acryloyl]-4-[3-(2-methyl- Methylcyclohexylamine cyclohexylamino)-propyl]- [1,4]diazepan-5-one 65 trans-1-[(E)-3-(3,4-Dichloro-phenyl)- trans-4-Amino-1-pyridin-2- 545.5 acryloyl]-4-[3-(4-hydroxy-4-pyridin- yl-cyclohexanol 2-yl-cyclohexylamino)-propyl]- (intermediate 13) [1,4]diazepan-5-one 66 trans-1-[(E)-3-(3,4-Dichloro-phenyl)- trans-4-Amino-cyclohexanol 468.5 acryloyl]-4-[2-(4-hydroxy- cyclohexylamino)propyl]- [1,4]diazepan-5-one 67 4-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)- Piperidine-4-carboxylic acid 510.2 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- ethyl ester propylamino)-cyclohexanecarboxylic acid ethyl ester 68 1-[(E)-3-(3,4-Dichloro-phenyl)- 3-Amino-propan-1-ol 428.2 acryloyl]-4-{3-[(3-hydroxy-propyl)- amino]-propyl}-[1,4]diazepan-5-one 69 1-[(E)-3-(3,4-Dichloro-phenyl)- 4-Hydroxy-4-pyrid-2- 531.2 acryloyl]-4-[3-(4′-hydroxy-3′,4′,5′,6′- yl(piperidine) tetrahydro-2′H-[2,4′]bipyridinyl-1′- yl)-propyl]-[1,4]diazepan-5-one 70 1-[(E)-3-(3,4-Dichloro-phenyl)- 4-Hydroxy-4-pyrid-3- 531.2 acryloyl]-4-[3-(4′-hydroxy-3′,4′,5′,6′- yl(piperidine) tetrahydro-2′H-[3,4′]bipyridinyl-1′- yl)-propyl]-[1,4]diazepan-5-one 71 (+/−)-1-[(E)-3-(3,4-Dichloro-phenyl)- (+/−) 3-Hydroxy-pyrollidine 440.2 acryloyl]-4-[3-(3-hydroxy-pyrrolidin- 1-yl)-propyl]-[1,4]diazepan-5-one 72 1-[(E)-3-(3,4-Dichloro-phenyl)- 4-Trifluoromethyl-piperidine 506.2 acryloyl]-4-[3-(4-trifluoromethyl- piperidin-1-yl)-propyl]- [1,4]diazepan-5-one 73 1-[(E)-3-(3,4-Dichloro-phenyl)- 1-Methanesulfonyl- 517.2 acryloyl]-4-[3-(4-methanesulfonyl- piperazine piperazin-1-yl)-propyl]- [1,4]diazepan-5-one 74 1-[(E)-3-(3,4-Dichloro-phenyl)- 4-Fluoro-piperidine 456.2 acryloyl]-4-[3-(4-fluoro-piperidin-1- yl)-propyl]-[1,4]diazepan-5-one 75 1-[(E)-3-(3,4-Dichloro-phenyl)- 1-Methyl-piperazine 517.2 acryloyl]-4-[3-(4-methyl-piperazin-1- yl)-propyl]-[1,4]diazepan-5-one 76 4-[3-(4-Methyl-4-hydroxy-piperidin- 4-Methyl-piperidin-4-ol 456.2 1-yl)-propyl]-1-[(E)-3-(3,4-dichloro- phenyl)-acryloyl]-[1,4]diazepan-5-one 77 4-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)- Piperidine-4-carboxylic acid 481.2 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- amide propylamino)-cyclohexanecarboxylic acid amide 78 1-[(E)-3-(3,4-Dichloro-phenyl)- Methyl-(tetrahydro-pyran-4- 468.2 acryloyl]-4-{3-[methyl-(tetrahydro- yl)-amine pyran-4-yl)-amino]-propyl}- [1,4]diazepan-5-one 79 1-[(E)-3-(3,4-Dichloro-phenyl)- 4-Methoxy-piperidine 468.3 acryloyl]-4-[3-(4-methoxy-piperidin- 1-yl)-propyl]-[1,4]diazepan-5-one 80 (+/−)-1-[(E)-3-(3,4-Dichloro-phenyl)- 3-Methoxy-piperidine 468.1 acryloyl]-4-[3-(3-methoxy-piperidin- 1-yl)-propyl]-[1,4]diazepan-5-one 81 (+/−)-1-[(E)-3-(3,4-Dichloro-phenyl)- (+/−) 3-Hydroxy-piperidine 454 acryloyl]-4-[3-(3-hydroxy-piperidin- 1-yl)-propyl]-[1,4]diazepan-5-one 82 [1-(3-{4-[(E)-3-(3,4-Dichloro- Ethyl piperidin-4-yl 525.1 phenyl)-acryloyl]-7-oxo- carbamate [1,4]diazepan-1-yl}-propyl)- piperidin-4-yl]-carbamic acid ethyl ester 83 N-[1-(3-{4-[(E)-3-(3,4-Dichloro- N-Piperidin-4-yl-acetamide 495.1 phenyl)-acryloyl]-7-oxo- [1,4]diazepan-1-yl}-propyl)- piperidin-4-yl]-acetamide 84 8-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)- Oxa-3,8-diaza- 509.3 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- spiro[4.5]decan-2- propyl)-1-oxa-3,8-diaza- one spiro[4.5]decan-2-one (intermediate 14) 85 1-[(E)-3-(3,4-Dichloro-phenyl)- 4-Oxazol-2-yl-piperidin-4-ol 521.0 acryloyl]-4-[3-(4-hydroxy-4-oxazol-2- hydrochloride yl-piperidin-1-yl)-propyl]- (intermediate 15) [1,4]diazepan-5-one 86 1-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)- Piperidine-4-carboxylic acid 495.0 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- methylamide propyl)-piperidine-4-carboxylic acid methylamide 87 8-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)- 2,8-Diaza-spiro[4.5]decane- 521.1 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- 1,3-dione propyl)-2,8-diaza-spiro[4.5]decane- (intermediate 17) 1,3-dione 88 8-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)- 2,8-Diaza-spiro[4.5]decan-3- 507.4 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- one propyl)-2,8-diaza-spiro[4.5]decan-3- (intermediate 18) one 89 8-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)- 1,3,8-Triaza-spiro[4.5]decan- 508.2 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- 4-one propyl)-1,3,8-triaza-spiro[4.5]decan- (intermediate 9) 4-one 90 1-(3-{4-[3-(3,4-Dichloro-phenyl)- 4-Hydroxy-piperidine-4- 497.2 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- carboxylic acid amide propyl)-4-hydroxy-piperidine-4- (intermediate 19) carboxylic acid amide 91 (R)-1-[(E)-3-(3,4-Dichloro-phenyl)- (R)-3-Hydroxypiperidine 454.2 acryloyl]-4-[3-(3-hydroxy-piperidin- 1-yl)-propyl]-[1,4]diazepan-5-one 92 (S)-1-[(E)-3-(3,4-Dichloro-phenyl)- (S)-3-Hydroxypiperidine 454.2 acryloyl]-4-[3-(3-hydroxy-piperidin- 1-yl)-propyl]-[1,4]diazepan-5-one

Examples 93-151 General Procedure for Examples 93-151

A solution of 3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-acetaldehyde (intermediate 3) (0.036 g, 0.1 mmol) in DCE (0.5 ml) was added to the appropriate amine (0.1 mmol) followed by a freshly prepared solution of pyridine-borane complex (25 ul, 8M in pyridine, 0.2 mmol) and acetic acid (25 ul) in EtOH (0.5 ml). The reaction was then shaken overnight, concentrated and the residue purified by preparative HPLC.

TABLE 4 Example MS: No. Compound Name Amine (MH⁺) 93 (S)-1-[(E)-3-(3,4-Dichloro-phenyl)- (S)-2-Methoxymethyl- 454.1 acryloyl]-4-[3-(2-methoxymethyl- pyrrolidine pyrrolidin-1-yl)-ethyl]-[1,4]diazepan-5- one 94 (R)-1-[(E)-3-(3,4-Dichloro-phenyl)- (R)-2-Methoxymethyl- 454.1 acryloyl]-4-[3-(2-methoxymethyl- pyrrolidine pyrrolidin-1-yl)-ethyl]-[1,4]diazepan-5- one 95 (R)-1-[(E)-3-(3,4-Dichloro-phenyl)- (R)-Prolinol 440.1 acryloyl]-4-[3-(2-hydroxymethyl- pyrrolidin-1-yl)-ethyl]-[1,4]diazepan-5- one 96 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- 4-Phenyl-piperidin-4-ol 516.5 4-[3-(4-hydroxy-4-phenyl-piperidin-1- yl)-ethyl]-[1,4]diazepan-5-one 97 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- 4-Methyl-piperidin-4-ol 454.4 4-[2-(4-hydroxymethyl-piperidin-1-yl)- ethyl]-[1,4]diazepan-5-one 98 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- 4-Hydroxy-4-pyrid-2- 517.5 4-[3-(4′-hydroxy-3′,4′,5′,6′-tetrahydro- yl(piperidine) 2′H-[2,4′]bipyridinyl-1′-yl)-ethyl]- [1,4]diazepan-5-one 99 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- 4-Hydroxy-4-pyrid-3- 517.5 4-[3-(4′-hydroxy-3′,4′,5′,6′-tetrahydro- yl(piperidine) 2′H-[3,4′]bipyridinyl-1′-yl)-ethyl]- [1,4]diazepan-5-one 100 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- 4-Hydroxy-4-pyrid-4- 517.5 4-[3-(4-hydroxy-3,4,5,6-tetrahydro-2H- yl(piperidine) [4,4′]bipyridinyl-1-yl)-ethyl]- [1,4]diazepan-5-one 101 1-(-3-{4-[(E)-3-(3,4-Dichloro-phenyl)- 4-Phenyl-piperidine-4- 525.5 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- carbonitrile ethyl)-4-phenyl-piperidine-4-carbonitrile 102 (+/−)-1-[(E)-3-(3,4-Dichloro-phenyl)- (+/−)-2- 438.4 acryloyl]-4-[3-(2-methyl-piperidin-1-yl)- Methylpiperidine ethyl]-[1,4]diazepan-5-one 103 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- Tetrahydro-pyran-4- 440.4 4-[3-(tetrahydro-pyran-4-ylamino)- ylamine ethyl]-[1,4]diazepan-5-one 104 cis/trans-1-[(E)-3-(3,4-Dichloro-phenyl)- cis/trans-2- 452.4 acryloyl]-4-[3-(2-methyl- Methylcyclohexylamine cyclohexylamino)-ethyl]-[1,4]diazepan-5- one 105 trans-1-[(E)-3-(3,4-Dichloro-phenyl)- trans-4-Amino-1- 531.5 acryloyl]-4-[3-(4-hydroxy-4-pyridin-2-yl- pyridin-2-yl- cyclohexylamino)-ethyl]-[1,4]diazepan-5- cyclohexanol one (intermediate 13) 106 trans-1-[(E)-3-(3,4-Dichloro-phenyl)- trans-4-Amino- 454.4 acryloyl]-4-[2-(4-hydroxy- cyclohexanol cyclohexylamino)-ethyl]-[1,4]diazepan-5- one 107 4-[3-(4-Cyclopropanecarbonyl-piperazin- Cyclopropyl-piperazin- 493.2 1-yl)-ethyl]-1-[(E)-3-(3,4-dichloro- 1-yl-methanone phenyl)-acryloyl]-[1,4]diazepan-5-one 108 4-[3-(Cyclopentyl-amino)-ethyl]-1-[(E)- Cyclopentylamine 424.2 3-(3,4-dichloro-phenyl)-acryloyl]- [1,4]diazepan-5-one 109 4-[-3-(Cyclopentyl-methyl-amino)- Cyclopentyl-methyl- 438.1 ethyl]-1-[(E)-3-(3,4-dichloro-phenyl)- amine acryloyl]-[1,4]diazepan-5-one 110 (+/−)-4-[3-(Bicyclo[2.2.1]hept-2- (+/−)-endo-2- 450.2 ylamino)ethyl]-1-[(E)-3-(3,4-dichloro- Norbonylamine phenyl)-acryloyl]-[1,4]diazepan-5-one hydrochloride 111 4-[3-(Cyclohexy-methyl-amino)-ethyl]-1- Cylcohexyl-methyl- 452.1 [(E)-3-(3,4-dichloro-phenyl)-acryloyl]- amine [1,4]diazepan-5-one 112 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- Thiomorpholine-1,1- 474.0 4-[3-(1,1-dioxo-thiomorpholin-4-yl)- dioxide ethyl]-[1,4]diazepan-5-one 113 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- (2-Methoxy-ethyl)- 428.1 4-{3-[(2-methoxy-ethyl)-methyl-amino]- methyl-amine ethyl}-[1,4]diazepan-5-one 114 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- (2-Hydroxy-ethyl)- 414.1 4-{3-[(2-hydroxy-ethyl)-methyl-amino]- methyl-amine ethyl}-[1,4]diazepan-5-one 115 4-{3-[Bis-(2-hydroxy-ethyl)-amino]- 2-(2-Hydroxy- 444.2 ethyl}-1-[(E)-3-(3,4-dichloro-phenyl)- ethylamino)-ethanol acryloyl]-[1,4]diazepan-5-one 116 (+/−)-N-[1-((E)-3-{4-[3-(3,4-Dichloro- (+/−)N-Pyrrolidin-3-yl- 467.2 phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1- acetamide yl}-ethyl)-pyrrolidin-3-yl]-acetamide 117 (S)-1-[(E)-3-(3,4-Dichloro-phenyl)- (S)-Prolinol 440.1 acryloyl]-4-[3-(2-hydroxymethyl- pyrrolidin-1-yl)-ethyl]-[1,4]diazepan-5- one 118 8-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)- 1,3,8-Triaza- 508.2 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- spiro[4.5]decane-2,4- ethyl)-1,3,8-triaza-spiro[4.5]decane-2,4- dione dione (intermediate 11) 119 4-[(E)-3-(4-Benzyl-4-hydroxy-piperidin- 4-Benzyl-piperidin-4-ol 530.1 1-yl)-ethyl]-1-[(E)-3-(3,4-dichloro- phenyl)-acryloyl]-[1,4]diazepan-5-one 120 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- 4-Methyl-piperidine 438.2 4-[3-(4-methyl-piperidin-1-yl)-ethyl]- [1,4]diazepan-5-one 121 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- Thiomorpholine 442.1 4-(3-thiomorpholin-4-yl-ethyl)- [1,4]diazepan-5-one 122 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- Morpholine 426.1 4-(2-morpholin-4-yl-ethyl)- [1,4]diazepan-5-one 123 (+/−)-1-[(E)-3-(3,4-Dichloro-phenyl)- (1,4)-Dioxan-2-yl- 470.1 acryloyl]-4-[3-([1,4]dioxan-2-ylmethyl- methylamine methyl-amino)-ethyl]-[1,4]diazepan-5- one 124 cis/trans-1-[(E)-3-(3,4-Dichloro-phenyl)- cis/trans-Methyl-(4- 466.3 acryloyl]-4-{3-[methyl-(4-methyl- methyl-cyclohexyl)- cyclohexyl)-amino]-ethyl}-[1,4]diazepan- amine 5-one 125 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- 4,4-Difluororpiperidine 460.1 4-[3-(4,4-difluoro-piperidin-1-yl)-ethyl]- [1,4]diazepan-5-one 126 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- Piperidin-4- 508.1 4-{3-[4-(2-oxo-imidazolidin-1-yl)- yl- piperidin-1-yl]-ethyl}-[1,4]diazepan-5- imidazolidin- one 2-one (intermediate 7) 127 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- 4-(1H-Pyrazol-3-yl)- 490.2 4-{3-[4-(1H-pyrazol-3-yl)-piperidin-1- piperidine yl]-ethyl}-[1,4]diazepan-5-one (intermediate 12) 128 4-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)- Piperidine-4-carboxylic 496.2 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- acid ethyl ester ethylamino)-cyclohexanecarboxylic acid ethyl ester 129 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- 4-Trifluoromethyl- 492.1 4-[3-(4-trifluoromethyl-piperidin-1-yl)- piperidine ethyl]-[1,4]diazepan-5-one 130 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- 4-Fluoro-piperidine 442.1 4-[3-(4-fluoro-piperidin-1-yl)-ethyl]- [1,4]diazepan-5-one 131 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- 1-Methyl-piperazine 439.2 4-[2-(4-methyl-piperazin-1-yl)-ethyl]- [1,4]diazepan-5-one 132 4-[3-(4-Methyl-4-hydroxy-piperidin-1- 4-Methyl-piperidin-4-ol 454.1 yl)-ethyl]-1-[(E)-3-(3,4-dichloro-phenyl)- acryloyl]-[1,4]diazepan-5-one 133 4-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)- Piperidine-4-carboxylic 467.1 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- acid amide ethylamino)-cyclohexanecarboxylic acid amide 134 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- Methyl-(tetrahydro- 454.2 4-{3-[methyl-(tetrahydro-pyran-4-yl)- pyran-4-yl)-amine amino]-ethyl}-[1,4]diazepan-5-one 135 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- 3-Amino-propan-1-ol 414.1 4-{3-[(3-hydroxy-propyl)-amino]-ethyl}- [1,4]diazepan-5-one 136 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- 1-Isopropyl-piperidin-4- 481.2 4-[2-(1-isopropyl-piperidin-4-ylamino)- ylamine ethyl]-[1,4]diazepan-5-one 137 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- 1-Methyl-piperidin-4- 453 4-[2-(1-methyl-piperidin-4-ylamino)- ylamine ethyl]-[1,4]diazepan-5-one 138 cis/trans-1-[(E)-3-(3,4-Dichloro-phenyl)- Cis/trans-4-Methyl- 452.1 acryloyl]-4-{3-[(4-methyl-cyclohexyl)- cyclohexylamine amino]-ethyl}-[1,4]diazepan-5-one 139 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- Piperidin-4-ol 440.1 4-[3-(4-hydroxy-piperidin-1-yl)-ethyl]- [1,4]diazepan-5-one 140 (+/−)-cis-1-[(E)-3-(3,4-Dichloro-phenyl)- (+/−)-cis-(3-Methoxy- 470.1 acryloyl]-4-{2-[(3-methoxy-tetrahydro- tetrahydro-pyran-4-yl)- pyran-4-yl)-amino]-ethyl}-[1,4]diazepan- amine 5-one (intermediate 20) 141 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- (R)-3- 440.2 4-[2-((R)-3-hydroxy-piperidin-1-yl)- Hydroxypiperidine ethyl]-[1,4]diazepan-5-one 142 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- (S)-3-Hydroxypiperidine 440.2 4-[2-((S)-3-hydroxy-piperidin-1-yl)- ethyl]-[1,4]diazepan-5-one 143 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- (R)-3-hydroxy- 426.1 4-[2-((R)-3-hydroxy-pyrrolidin-1-yl)- pyrrolidine ethyl]-[1,4]diazepan-5-one 144 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- (S)-3-hydroxy- 426.1 4-[2-((S)-3-hydroxy-pyrrolidin-1-yl)- pyrrolidine ethyl]-[1,4]diazepan-5-one 145 (S)-1-(2-{4-[(E)-3-(3,4-Dichloro-phenyl)- (S)-pyrrolidine-2- 467.2 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- carboxylic acid ethyl)-pyrrolidine-2-carboxylic acid methylamide methylamide 146 (S)-1-(2-{4-[(E)-3-(3,4-Dichloro-phenyl)- (S)-pyrrolidine-2- 453.1 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- carboxylic acid amide ethyl)-pyrrolidine-2-carboxylic acid amide 147 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- (S)-3-ethoxy-pyrrolidine 454.2 4-[2-((S)-3-ethoxy-pyrrolidin-1-yl)- ethyl]-[1,4]diazepan-5-one 148 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- (2S,4R)-4-hydroxy-2- 456.1 4-[2-((2S,4R)-4-hydroxy-2- hydroxymethyl- hydroxymethyl-pyrrolidin-1-yl)-ethyl]- pyrrolidine [1,4]diazepan-5-one (intermediate 21) 149 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- (2S,4S)-4-hydroxy-2- 456.1 4-[2-((2S,4S)-4-hydroxy-2- hydroxymethyl- hydroxymethyl-pyrrolidin-1-yl)-ethyl]- pyrrolidine [1,4]diazepan-5-one (intermediate 22) 150 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]- (2R,3S)-3-hydroxy-2- 456.1 4-[2-((2R,3S)-3-hydroxy-2- hydroxymethyl- hydroxymethyl-pyrrolidin-1-yl)-ethyl]- pyrrolidine [1,4]diazepan-5-one 151 (2S,3S)-1-(2-{4-[(E)-3-(3,4-Dichloro- (2S,3S)-3-hydroxy- 484.1 phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1- pyrrolidine-2-carboxylic yl}-ethyl)-3-hydroxy-pyrrolidine-2- acid methyl ester carboxylic acid methyl ester

Example 152 (+/−)-cis-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-{2-[(3-methoxy-tetrahydro-pyran-4-yl)-methyl-amino]-ethyl}-[1,4]diazepan-5-one

To the crude reaction mixture from (+/−)-cis-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-{2-[(3-methoxy-tetrahydro-pyran-4-yl)-amino]-ethyl}-[1,4]diazepan-5-one (example 140) was added 2 drops of 36% aqueous formaldehyde solution and the mixture shaken for 1 h. The reaction was then concentrated and the residue purified by flash column chromatography (CH₂Cl₂:MeOH 1:0-8:2) affording the titled product (21 mg, 44%) as a colourless solid. MS: 484.1 (MH⁺, 2Cl).

Example 153 8-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propyl)-8-methyl-2,4-dioxo-1,3-diaza-8-azonia-spiro[4.5]decane iodide

To a solution of 8-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione (example 48) (10 mg, 19 umol) in MeOH (0.5 ml) was added iodomethane (10 uL, 95 umol) and the reaction left for 2 days at room temperature. Concentration of the mixture affording the title product (13 mg, 98%) as a white solid. MS: 536.1 (M⁺, 2Cl).

Example 154 1-(3-{4-[3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propyl)-1-methyl-piperidinium iodide

To a solution of 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one (example 4) (27 mg, 62 umol) in MeOH (0.5 ml) was added iodomethane (40 uL, 620 umol) and the reaction left for overnight at room temperature. Concentration of the mixture affording the title product (35 mg, 98%) as a white solid. MS: 452.2 (M⁺, 2Cl).

Example 155 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(4-morpholin-4-yl-butyl)-[1,4]diazepan-5-one 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(4-morpholin-4-yl-butyl)-[1,4]diazepan-5-one

In analogy to the procedure described in example 5D, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one (example 9C) and morpholine (10 eq, with no additional sodium iodide) gave the title compound as light yellow oil. MS: 454.2 (MH⁺, 2Cl).

Example 156 1-[(E)-(3-Phenyl-acryloyl)]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one 1-[(E)-(3-Phenyl-acryloyl)]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one

In analogy to the procedure described in example 11A, 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4B) and (E)-cinnamic acid gave the title compound as off-white solid. MS: 370.2 (MH⁺).

Example 157 1-((E)-3-Naphthalen-2-yl-acryloyl)-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one 1-((E)-3-Naphthalen-2-yl-acryloyl)-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one

In analogy to the procedure described in example 11A, 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4B) and 2-naphthylacrylic acid gave the title compound as white solid. MS: 420.2 (MH⁺)

Example 158 4-(1-Benzyl-piperidin-4-yl)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one {2-[Acryloyl-(1-benzyl-piperidin-4-yl)-amino]-ethyl}-carbamic acid tert-butyl ester

To a solution of benzylpiperidone (5 g, 26 mmol) and (2-amino-ethyl)-carbamic acid tert-butyl ester (4.23 g, 26 mmol) and acetic acid (2.5 ml, 53 mmol) in CH₂Cl₂ (50.0 ml) was slowly added NaBH(OAc)₃ (6.69 g, 32 mmol). On completion of the addition the reaction was stirred for 0.5 h. Saturated NaHCO₃ (30 ml) was then cautiously added until the pH was basic. A solution of acrolyl chloride (2.3 ml, 29 mmol) in CH₂Cl₂ (10.0 ml) was then added and the reaction stirred for a further 1 h. The organic layer was then separated, dried (Na₂SO₄) and concentrated. The product was isolated by flash column chromatography (EtOAc) to afford the title compound as a light yellow foam (6 g, 58%). MS: 388.2 (MH⁺).

4-(1-Benzyl-piperidin-4-yl)-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester

To a solution of {2-[Acryloyl-(1-benzyl-piperidin-4-yl)-amino]-ethyl}-carbamic acid tert-butyl ester (4.6 g, 12 mmol) in DMF (40 ml) was added potassium tert-butoxide (0.1 g, 1 mmol) and the reaction stirred for 2 h after which time it was concentrated, the residue dissolved in CH₂Cl₂, washed with saturated NaHCO₃, dried (Na₂SO₄), and concentrated. The product was isolated by flash column chromatography (CH₂Cl₂:MeOH 9:1) to afford the title compound (3.5 g, 75%) as a white solid. MS: 388.3 (MH⁺)

4-(1-Benzyl-piperidin-4-yl)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one

4-(1-Benzyl-piperidin-4-yl)-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.5 g, 4 mmol) was dissolved in trifluoroacetic acid (10 ml) and the reaction stirred for 1 h. The reaction was concentrated to dryness, portioned between CH₂Cl₂ (20 ml) and saturated NaHCO₃ (20 ml) and a solution of (E)-3-(3,4-dichloro-phenyl)-acryloyl chloride (prepared by Vilsmeier-Heck reaction on the acid) (0.9 g, 4 mmol) in CH₂Cl₂ (10 ml) was added dropwise. The reaction was stirred for 0.5 h after which time the organic was collected, dried (Na₂SO₄), and concentrated to afford the title compound (1.8 g, 92%) as a white solid. MS: 486.9 (MH⁺, 2Cl).

Example 159 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[3-(4-hydroxy-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one

In analogy to examples 35-91, 3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propionaldehyde (intermediate 2) was reacted with piperidine-4-ol to afford the title product as a white solid. MS: 454.4 (MH⁺, 2Cl).

Example 160 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(2-pyrrolidin-1-yl-ethyl)-[1,4]diazepan-5-one

In analogy to examples 14-26, 4-(2-pyrrolidin-1-yl-ethyl)-[1,4]diazepan-5-one-dihydrochoride (intermediate 5) was reacted with 3,4-dichlorocinammic acid to afford the title compound as a white solid. MS: 410.3 (MH⁺, 2Cl).

Example 161 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[4-(3-hydroxy-piperidin-1-yl)-butyl]-[1,4]diazepan-5-one (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[4-(3-hydroxy-piperidin-1-yl)-butyl]-[1,4]diazepan-5-one

In analogy to the procedure described in example 5D, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(3-iodo-propyl)-[1,4]diazepan-5-one and (rac)-3-hydroxy-piperidine (10 equivalents, with no additional sodium iodide) gave after purification on a flash isolute NH₂-column (n-heptane/EtOAc 1:4 to 1:9 and EtOAc) the title compound as a light yellow oil. MS: 468.1 (MH⁺, 2Cl).

Example 162 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(5-piperidin-1-yl-pentyl)-[1,4]diazepan-5-one 4-(5-Chloro-pentyl)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one

In analogy to the procedure described in example 5A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) and 1-chloro-5-iodopentane gave the title compound as yellow oil. MS: 416.9 (MH⁺, 3Cl).

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(5-iodo-pentyl)-[1,4]diazepan-5-one

In analogy to the procedure described in example 6D, 4-(5-chloro-pentyl)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one and sodium iodide were stirred at 90° C. for 20 h to give the title compound as orange oil. MS: 509.2 (MH⁺, 2Cl).

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(5-piperidin-1-yl-pentyl)-[1,4]diazepan-5-one

In analogy to the procedure described in example 5D, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(5-iodo-pentyl)-[1,4]diazepan-5-one and piperidine (10 equivalents, with no additional sodium iodide) gave the title compound as yellow oil. MS: 466.2 (MH⁺, 2Cl).

Example 163 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[4-((3RS,4SR)-3,4-dihydroxy-piperidin-1-yl)-butyl]-[1,4]diazepan-5-one hydrochlorid 4-{4-[(3RS,4SR)-3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-piperidin-1-yl]-butyl}-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one

A solution of 0.279 g (0.56 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one (example 9B) in 2 ml of DMA was treated with 0.195 ml (0.56 mmol) of (cis)-(rac)-3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-piperidine (intermediate 25) and 0.184 g (0.56 mmol) of cesium carbonate. After 2.25 h at RT, CH₂Cl₂ was added, filtrated and evaporated. Purification by catridges, Si-Amine, 50 g, (EtOAc/n-heptane 4:1) gave 0.300 g (75%) of the title compound as light brown foam. MS: 712.6 (MH⁺, 2Cl).

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[4-((3RS,4SR)-3,4-dihydroxy-piperidin-1-yl)-butyl]-[1,4]diazepan-5-one hydrochlorid

A solution of 0.100 g (0.14 mmol) of 4-{4-[(3RS,4SR)-3,4-bis-(tert-butyl-dimethyl-silanyloxy)-piperidin-1-yl]-butyl}-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one in 2 mL of MeOH was cooled (0° C.), treated with 0.35 ml (1.40 mmol) of 4M HCl in dioxane and stirred at RT for 2 h. The solution was evaporated, dissolved in toluene and evaporated (2×) to yield 0.053 g (73%) of the title compound as light brown foam. MS: 484.2 (MH⁺, 2Cl).

Example 164 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[4-((3RS,4RS)-3,4-dihydroxy-piperidin-1-yl)-butyl]-[1,4]diazepan-5-one hydrochloride 4-{4-[(3RS,4RS)-3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-piperidin-1-yl]-butyl}-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one

In analogy to the procedure described in example 163A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one (example 9B) and (trans)-(rac)-3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-piperidine (intermediate 26) gave the title compound as colorless oil.

MS: 712.5 (MH⁺, 2Cl).

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[4-((3RS,4RS)-3,4-dihydroxy-piperidin-1-yl)-butyl]-[1,4]diazepan-5-one hydrochloride

In analogy to the procedure described in example 163B, 4-{4-[(3RS,4RS)-3,4-bis-(tert-butyl-dimethyl-silanyloxy)-piperidin-1-yl]-butyl}-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one gave the title compound as off-white solid. MS: 484.4 (MH⁺, 2Cl).

Example 165 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[4-((3RS,4RS)-3,4-dihydroxy-piperidin-1-yl)-butyl]-[1,4]diazepan-5-one 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[4-((3RS,4RS)-3,4-dihydroxy-piperidin-1-yl)-butyl]-[1,4]diazepan-5-one

A solution of 0.025 g (0.05 mmol) 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-[4-((3RS,4RS)-3,4-dihydroxy-piperidin-1-yl)-butyl]-[1,4]diazepan-5-one was dissolved in EtOAc and washed with aqueous saturated NaHCO₃. The water phase was extracted with EtOAc(2×), the organic phases washed with aqueous saturated NaHCO₃, dried over Na₂SO₄ and evaporated to give 0.017 g (73%) of the title compound as colorless foam. MS: 484.2 (MH⁺, 2Cl).

Example 166 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(2-hydroxy-3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-oxiranylmethyl-1,41diazepan-5-one

A solution of 1.50 g (4.79 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A) in 30 ml of DMF, with 0.29 g (6.71 mmol) of NaH (55% in oil) was stirred for 30 min at 0° C. and then treated slowly with 0.47 ml (5.75 mmol) of 2-bromomethyl-oxirane in 15 ml DMF. After 3.5 h at 0° C., the reaction was extracted with aqueous saturated NaHCO₃/EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO₃, dried over Na₂SO₄ and evaporated to yield 2.79 g (quantitative) of the crude title compound as off-white semisolid, which was used directly in the next steps. MS: 368.9 (MH⁺, 2Cl).

(rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(2-hydroxy-3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one

A solution of 0.30 g (0.81 mmol) of (rac)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-oxiranylmethyl-[1,4]diazepan-5-one in 0.3 ml of DMA was treated with 0.19 ml (1.22 mmol) of piperidine and 0.265 g (0.81 mmol) of cesium carbonate. The reaction was stirred over night at RT, CH₂Cl₂ was added, filtrated and evaporated. Crystallization (CH₂Cl₂/Et₂O) gave 0.16 g (43%) of the title compound as pink crystalline solid. MS: 454.2 (MH⁺, 2Cl).

Example 167 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-((S)-2-hydroxy-3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-[1,4]diazepan-5-one

A solution of 6.26 g (20.00 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) in 200 ml of THF was treated at 0° C. with 2.47 g (22.00 mmol) of potassium tert-butylate and after 10 min with 5.73 (20.00 mmol) of toluene-4-sulfonic acid (S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester. The reaction was stirred for 14 h at RT, 28 h at reflux temperature, cooled and extracted with aqueous saturated NaHCO₃/Et₂O (3×). The organic phases were washed with aqueous saturated NaHCO₃, aqueous 10% NaCl, dried over Na₂SO₄ evaporated and purified by flash silica gel column (CH₂Cl₂/MeOH 97.5/2.5) to yield 4.27 g (50%) of the title compound as off-white powder. MS: 427.1 (MH⁺, 2Cl).

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-((R)-2,3-dihydroxy-propyl)-[1,4]diazepan-5-one

A solution of 4.16 g (9.72 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-[1,4]diazepan-5-one in 35 ml of methanol and 3.8 ml of water was treated with 1.95 g of Dowex 50WX8 (activated with aqueous 25% HCl and washed neutral wit water). The reaction was stirred for 10 h at reflux temperature, cooled, evaporated, dissolved in CH₂Cl₂, dried over Na₂SO₄ and evaporated to yield 3.37 g (89%) of the title compound as light yellow foam. MS: 387.1 (MH⁺, Cl).

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(R)-1-oxiranylmethyl-[1,4]diazepan-5-one

An ice-cooled solution of 0.50 g (1.30 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-((R)-2,3-dihydroxy-propyl)-[1,4]diazepan-5-one and 1.72 ml (13.00 mmol) of 2,4,6-trimethyl-pyridine in 5.2 ml of DMF was treated with 0.11 ml (1.36 mmol) of methanesulfonyl chloride in 0.3 mL of DMF. The reaction was stirred 2.5 h at 0° C. and 1 h at RT. After cooling (0° C.), 0.13 g (2.86 mmol) of NaH (55% in oil) was added and the reaction was continued at this temperature for 16 h. The solution was poured on cold aqueous 10% KH₂PO₄ and extracted with Et₂O (3×). The organic phases were washed with aqueous 10% KH₂PO₄ (2×), aqueous saturated NaHCO₃ and aqueous 10% NaCl, dried (Na₂SO₄) and concentrated to yield after precipitation (CH₂Cl₂/n-pentane) 0.38 g (78%) of the title compound as light yellow powder. MS: 368.9 (MH⁺, 2Cl).

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-((S)-2-hydroxy-3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one

A suspension of 0.10 g (0.27 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(R)-1-oxiranylmethyl-[1,4]diazepan-5-one in 0.27 ml of EtOH was treated at 0° C. with 0.04 ml (0.40 mmol) of piperidine. The reaction was stirred for 20 h at RT, then evaporated, suspended in toluene and evaporated again. Precipitation (CH₂Cl₂/Et₂O/-n-pentane) gave 0.10 g (84%) of the title compound as off-white powder with 90% ee. MS: 454.1 (MH⁺, 2Cl). (The enatiomeric purity was determined with a chiralpak-ADH column, 25 cm*4.6 mm, No.DL182 and 30% n-heptane+70% (EtOH+0.01M NH₄AcOH) as eluent. The purity corresponds to the purity of toluene-4-sulfonic acid (S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester).

Example 168 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-((R)-2-hydroxy-3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-((R)-2-hydroxy-3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one

135 mg of (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-((S)-2-hydroxy-3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one (example 166) were separated with a chiralpak-ADH column, 5 μM, 25 cm*20 mm, Daicel, Cat.-No. 19345 and 25% n-heptane+75% (EtOH/MeOH 25:75 v/v) as eluent. 48.9 mg (36%) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-((S)-2-hydroxy-3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one (99.4% ee) (example 167D) and 50 mg (37%) of 1-[(E)-3-( 3,4-dichloro-phenyl)-acryloyl]-4-((R)-2-hydroxy-3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one (99.6% ee) was isolated as a white foam. MS: 454.1 (MH⁺, 2Cl). (The enatiomeric purity was determined with a chiralpak-ADH column, Daicel, Cat.-No. 19325, 25 cm*4.6 mm and 35% n-heptan+65% EtOH as eluent).

Example 169 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[3-(4-fluoro-piperidin-1-yl)-2-hydroxy-propyl]-[1,4]diazepan-5-one (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[3-(4-fluoro-piperidin-1-yl)-2-hydroxy-propyl]-[1,4]diazepan-5-one

A solution of 0.080 g (0.22 mmol) of (rac)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-oxiranylmethyl-[1,4]diazepan-5-one (example 166A) in 0.5 ml of MeOH was treated with 0.038 (0.26 mmol) of 4-fluoropiperidine hydrochloride and 0.15 ml (1.08 mmol) of Et₃N in 0.5 ml of MeOH. The reaction was stirred for 24 h at RT, partitioned between aqueous saturated NaHCO₃ and extracted with Et₂O (3×). The organic phase was dried over Na₂SO₄ and evaporated to give after flash silica gel column (CH₂Cl₂/MeOH 98:2) 0.0099 g (10%) of the title compound as white foam. MS: 471.9 (MH⁺, 2Cl).

Example 170 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(3-hydroxy-4-piperidin-1-yl-butyl)-[1,4]diazepan-5-one (rac) 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(2-oxiranyl-ethyl)-[1,4]diazepan-5-one

In analogy to the procedure described for example 166A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A) and (rac)-2-(2-bromo-ethyl)-oxirane (Journal of Organic Chemistry (1969), 34(12), 4060-5) gave after extraction with Et₂O instead of EtOAc the title compound as yellow oil. MS: 383.2 (MH⁺, 2Cl).

(rac) 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(3-hydroxy-4-piperidin-1-yl-butyl)-[1,4]diazepan-5-one

In analogy to the procedure described for example 167D, (rac)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(2-oxiranyl-ethyl)-[1,4]diazepan-5-one and piperidine gave the title compound as yellow oil. MS: 468.1 (MH⁺, 2Cl).

Example 171 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[3-hydroxy-4-(3-hydroxy-piperidin-1-yl)-butyl]-[1,4]diazepan-5-one (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[3-hydroxy-4-(3-hydroxy-piperidin-1-yl)-butyl]-[1,4]diazepan-5-one

In analogy to the procedure described for example 167D, (rac)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(2-oxiranyl-ethyl)-[1,4]diazepan-5-one and 3-hydroxypiperidine gave the title compound as yellow oil. MS: 484.2 (MH⁺, 2Cl).

Example 172 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-((R)-3-hydroxy-4-piperidin-1-yl-butyl)-[1,4]diazepan-5-one 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-[1,4]diazepan-5-one

In analogy to the procedure described for example 167A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) and methanesulfonic acid 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester (prepared from 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethanol and methanesulfonyl chloride) gave after reaction at RT, the title compound as an off-white foam. MS: 441.1 (MH⁺, 2Cl).

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-((R)-3,4-dihydroxy-butyl)-[1,4]diazepan-5-one

In analogy to the procedure described for example 167B, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-[2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-[1,4]diazepan-5-one gave after 3 h at reflux, the title compound as a white foam. MS: 401.2 (MH⁺, 2Cl).

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-((R)-2-oxiranyl-ethyl)-[1,4]diazepan-5-one

In analogy to the procedure described for example 167C, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-((R)-3,4-dihydroxy-butyl)-[1,4]diazepan-5-one gave the title compound as an off-white foam. MS: 383.0 (MH⁺, 2Cl).

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-((R)-3-hydroxy-4-piperidin-1-yl-butyl)-[1,4]diazepan-5-one

In analogy to the procedure described for example 167D, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-((R)-2-oxiranyl-ethyl)-[1,4]diazepan-5-one the title compound as an white foam with 94% ee. MS: 368.3 (MH⁺, 2Cl). (The enatiomeric purity was determined with a chiralpak-ADH column, 25 cm*4.6 mm, No.DL182 and 50% n-heptan+50% (EtOH+0.01M NH₄AcOH) as eluent. The purity corresponds to the purity of 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethanol).

Example 173 1-((Z)-3-Naphthalen-1-yl-acryloyl)-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one 1-((Z)-3-Naphthalen-1-yl-acryloyl)-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one

In analogy to the procedure described for example 11A, 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4B) and (Z)-3-naphthalen-1-yl-acrylic acid gave the title compound as light yellow foam. MS: 420.1 (MH⁺).

Example 174 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(2,2-dimethyl-3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one 2,2-Dimethyl-3-piperidin-1-yl-propan-1-ol

A solution of 3.00 g (17.96 mmol) of 3-bromo-2,2-dimethyl-propan-1-ol, 17.78 ml (179.59 mmol) of piperidine, 2.48 g (17.96 mmol) of K₂CO₃ and 2.69 g (17.96 mmol) of potassium iodide in 20 ml of DMA were stirred at 70° C. for 20 h. After filtration and evaporation of the solvents, the crude product was dissolved in diluted aqueous HCl solution and washed with EtOAc (3×). The aqueous phase was basified with KHCO₃ and some drops of 1N NaOH and extracted with EtOAc (3×). The organic phase was dried (Na₂SO₄) and evaporated to give 0.57 g (18%) of the title compound as yellow liquid. MS: 172.0 (MH⁺).

Methanesulfonic acid 2,2-dimethyl-3-piperidin-1-yl-propyl ester

A solution of 0.51 g (2.99 mmol) of 2,2-dimethyl-3-piperidin-1-yl-propan-1-ol in 7 ml of dichloromethane was treated at 0° C. with 0.24 ml (179.59 mmol) of methanesulfonyl chloride and stirred at RT for 2.5 h. The reaction was extracted with aqueous saturated NaHCO₃ /Et₂O (3×). The organic phases were washed with aqueous saturated NaHCO₃, dried over Na₂SO₄ and evaporated to give 0.85 g (quantitative) of the title compound as light brown oil. MS: 249.2 (M⁺).

1-(3-Iodo-2,2-dimethyl-propyl)-piperidine

In analogy to the procedure described for example 6D, methanesulfonic acid 2,2-dimethyl-3-piperidin-1-yl-propyl ester and sodium iodide stirred at 95° C. for 3 h gave the title compound as brown oil. MS: 282.1 (MH⁺).

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(2,2-dimethyl-3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one

In analogy to the procedure described for intermediate 4A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) and 1-(3-iodo-2,2-dimethyl-propyl)-piperidine stirred 2 h at RT, gave the title compound as white solid. MS: 466.3 (MH⁺, 2Cl).

Example 175 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-((S)-2-hydroxy-3-piperidin-1-yl-propyl)-[1,4]diazep an-5-one 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-(R)-1-oxiranylmethyl-[1,4]diazepan-5-one

In analogy to the procedure described for example 167A to 167C, 1-[(E)-3-(3-chloro-4-fluoro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 54) and toluene-4-sulfonic acid (S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester gave the title compound as light yellow viscous oil.

MS: 353.1 (MH⁺, 1Cl).

1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-((S)-2-hydroxy-3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one

In analogy to the procedure described for example 167D, 1-[(E)-3-(3-chloro-4-fluoro-phenyl)-acryloyl]-4-(R)-1-oxiranylmethyl-[1,4]diazepan-5-one and piperidine gave the title compound as off-white foam. MS: 438.3 (MH⁺, 1Cl).

Example 176 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(2-hydroxy-2-methyl-3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(2-hydroxy-2-methyl-3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one

In analogy to the procedure described for example 166, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A) and 2-chloromethyl-2-methyloxirane with 0.3 equivalent of potassium iodide gave the intermediate 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(2-methyl-oxiranylmethyl)-[1,4]diazepan-5-one which was reacted with no work up with piperidine in ethanol to give the title compound as light yellow waxy solid. MS: 468.2 (MH⁺, 2Cl).

Example 177 (rac)-1-[(E)-3-(3,4-Difluoro-phenyl)-acryloyl]-4-(2-hydroxy-3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one (rac)-1-[(E)-3-(3,4-Difluoro-phenyl)-acryloyl]-4-oxiranylmethyl-[1,4]diazepan-5-one

In analogy to the procedure described for example 166A, 1-[(E)-3-(3,4-difluoro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 55) and 2-bromomethyl-oxirane gave the title compound as yellow oil. MS: 337.2 (MH⁺).

(rac)-1-[(E)-3-(3,4-Difluoro-phenyl)-acryloyl]-4-(2-hydroxy-3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one

In analogy to the procedure described for example 166B, (rac)-1-[(E)-3-(3,4-difluoro-phenyl)-acryloyl]-4-oxiranylmethyl-[1,4]diazepan-5-one and piperidine gave the title compound as light yellow viscous oil. MS: 422.2 (MH⁺).

Example 178 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-((S)-3-hydroxy-4-piperidin-1-yl-butyl)-[1,4]diazepan-5-one 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-((S)-3,4-dihydroxy-butyl)-[1,4]diazepan-5-one

In analogy to the procedure described for example 167A and 167B, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) and methanesulfonic acid 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester (prepared from 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethanol and methanesulfonyl chloride) gave the title compound as an white foam. MS: 401.3 (MH⁺, 2Cl).

Methanesulfonic acid (S)-4-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-2-hydroxy-butyl ester

In analogy to the procedure described for example 167C, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-((S)-3,4-dihydroxy-butyl)-[1,4]diazepan-5-one with 2,4,6-trimethyl-pyridine and methanesulfonyl chloride in CH₂Cl₂ gave the intermediate mesylate as an white foam. MS: 479.0 (MH⁺, 2Cl).

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-((S)-3-hydroxy-4-piperidin-1-yl-butyl)-[1,4]diazepan-5-one

In analogy to the procedure described for example 166B, Methanesulfonic acid (S)-4-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-2-hydroxy-butyl ester with catalytic amount of sodium iodide, 1.2 equivalent of cesium carbonate and 5 equivalent of piperidine gave after 2 h at 60° C. the epoxide as intermediate. A further equivalent of cesium carbonate was added and the reaction heated at 80° C. over night to give the title compound as a colorless gum with 99% ee. MS: 368.1 (MH⁺, 2Cl). (The enatiomeric purity was determined with a chiralpak-ADH column, 25 cm*4.6 mm, No.DL182 and 50% n-heptane+50% (EtOH+0.01M NH₄AcOH) as eluent. The purity corresponds to the purity of 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethanol).

Example 179 (rac)-2-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-5-piperidin-1-yl-pentanoic acid methyl ester (rac)-5-Bromo-2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-pentanoic acid methyl ester

A solution of 0.501 g (1.60 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A) and 0.447 g (1.60 mmol) of methyl 2,5-dibromopentane in 7 ml of DMF was treated at 0° C. with 0.077 g (1.76 mmol) of NaH (55% in oil). The reaction was stirred for 20 h at RT, cooled (0° C.) and treated again with 0.224 g (0.80 mmol) of methyl 2,5-dibromopentane and 0.038 g (0.88 mmol) of NaH (55% in oil). After 1 h at 0° C. and 3 h at RT, the reaction was neutralized with cold aqueous 10% KHSO₄ and extracted with Et₂O (3×). The organic phases were washed with aqueous 10% KHSO₄, aqueous 10% NaCl, dried over Na₂SO₄ evaporated and purified by flash silica gel column (CH₂Cl₂/Et₂O 95:5 to 70:30) to yield 0.39 g (48%) of the title compound as white foam. MS: 505.1 (MH⁺, 1Br).

(rac)-2-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-5-iodo-pentanoic acid methyl ester

In analogy to the procedure described in example 6D, 4-(5-chloro-pentyl)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one and sodium iodide were stirred at RT for 4 h to give the title compound as yellow foam. MS: 552.2 (MH⁺, 2Cl).

(rac)-2-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-5-piperidin-1-yl-pentanoic acid methyl ester

A solution of 0.111 g (0.20 mmol) of 2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-5-iodo-pentanoic acid methyl ester in 1 ml of DMA was treated at 0° C. with 0.021 ml (0.21 mmol) of piperidine and stirred 30 min at 0° C. and 1 h at RT. 0.065 g (0.20 mmol) of cesium carbonate was added at 0° C. and stirring was continued for 2 h. After additional 3 h at RT, the reaction was extracted with aqueous saturated NaHCO₃/Et₂O (3×). The organic phases were washed with aqueous saturated NaHCO₃, aqueous 10% NaCl, dried over Na₂SO₄ evaporated and precipitated with CH₂Cl₂/n-pentane to yield 0.86 g (84%) of the title compound as a white foam. MS: 510.3 (MH⁺, 2Cl).

Example 180 Lithium; (rac)-2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-5-piperidin-1-yl-pentanoate Lithium; (rac)-2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl]}-5-piperidin-1-yl-pentanoate

A solution of 0.041 g (0.08 mmol) of the above prepared (rac)-2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-5-piperidin-1-yl-pentanoic acid methyl ester in 4 ml of THF/MeOH (1:1), treated at 0° C. with 0.084 mL (0.08 mmol) of 1 N LiOH, and kept at ambient temperature for 20 h. Water (0.32 ml) was added and heated for 1 h at 40° C. The reaction was evaporated and precipitated with CH₂Cl₂/Et₂O to give 0.028 g (70%) of the title compound as white powder. MS: 494.2 (M−H⁻, 2Cl).

Example 181 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(1-hydroxymethyl-4-piperidin-1-yl-butyl)-[1,4]diazepan-5-one (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(1-hydroxymethyl-4-piperidin-1-yl-butyl)-[1,4]diazepan-5-one

A solution of 0.041 g (0.08 mmol) of (rac)-2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-5-piperidin-1-yl-pentanoic acid methyl ester in 0.5 ml of ethanol was treated at 0° C. with 0.006 g (0.16 mmol) of sodium borohydride in 0.5 ml of ethanol during 5 min. The reaction was stirred for 21 h at RT, cooled (0° C.) and treated again with 0.006 g (0.16 mmol) of sodium borohydride in 0.5 ml ethanol. After 5 h at RT the reaction was neutralized with cold aqueous 10% KHSO₄ and extracted with cold saturated NaHCO₃/EtOAc (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na₂SO₄, evaporated and purified by flash silica gel column (CH₂Cl₂/MeOH 9:1 to 4:1 and then, to elute the product, with CH₂Cl₂/MeOH/25% NH₄OH 9:1:0.1) to yield after precipitation with CH₂Cl₂/n-penatne 0.022 g (57%) of the title compound as white foam. MS: 482.3 (MH⁺, 2Cl).

Example 182 (rac)-3-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-2-piperidin-1-ylmethyl-propionic acid ethyl ester 2-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-ylmethyl}-acrylic acid ethyl ester

A suspension of 2.50 g (7.98 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A) and 1.15 ml (7.98 mmol) of ethyl 2-(bromomethylacrylate) in 80 ml of DMF was treated at −20° C. with 0.38 g (8.78 mmol) of NaH (55% in oil) and warmed up naturally to 18° C. (2.5 h). After cooling (0° C.) additionally 0.12 ml (0.80 mmol) of ethyl 2-(bromomethylacrylate) was added and after 30 min no starting material was left, based on TLC. The reaction was extracted with aqueous 10% KHSO₄/ether (3×), the organic phases were washed with a aqueous 10% NaCl solution, dried (Na₂SO₄) and evaporated to give 3.51 g (quantitative, 90% purity) of the crude title compound as light yellow viscous oil, which was used directly in the next step. MS: 425.1 (MH⁺, 2Cl).

(rac)-3-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-2-piperidin-1-ylmethyl-propionic acid ethyl ester

A suspension of 0.80 g (1.88 mmol) of 2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-ylmethyl}-acrylic acid ethyl ester, 0.56 ml (5.64 mmol) of piperidine and 1.83 g (5.61 mmol) of cesium carbonate in 32 ml of acetonitrile was stirred over night at RT. Additional 0.37 ml (3.76 mmol) of piperidine were added and after 1 h, cesium carbonate was filtrated and the solvent evaporated. Purification by flash silica gel column (CH₂Cl₂/MeOH 98:2 to 96:4) gave 0.43 g (44%) of the title compound as colorless foam. MS: 510.4 (MH⁺, 2Cl).

Example 183 Lithium; (rac)-3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-2-piperidin-1-ylmethyl-propionate Lithium; (rac)-3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-2-piperidin-1-ylmethyl-propionate

In analogy to the procedure described in example 180, (rac)-3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-2-piperidin-1-ylmethyl-propionic acid ethyl ester gave the title as colorless solid. MS: 480.1 (M−H⁻, 2Cl).

Examples 184-187

The following examples were produced from the appropriate [1,4]-diazepan-5-one derivative and 1-(3-chloropropyl)piperidine in analogy to the procedure described in intermediate 4A:

Example [1,4]-diazepan-5-one MS: No. Compound Name derivative (MH⁺) 184 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-1-[(E)-3-(3,4-Dichloro- 452.2 acryloyl]-3-methyl-4-(3-piperidin-1- phenyl)-acryloyl]-3-methyl- yl-propyl)-[1,4]diazepan-5-one [1,4]diazepan-5-one (Intermediate 77) 185 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-1-[(E)-3-(3,4-Dichloro- 452.1 acryloyl]-7-methyl-4-(3-piperidin-1- phenyl)-acryloyl]-7-methyl- yl-propyl)-[1,4]diazepan-5-one [1,4]diazepan-5-one (Intermediate 78) 186 (R)-1-[(E)-3-(3,4-Dichloro-phenyl)- (R)-1-[(E)-3-(3,4-Dichloro- 452.1 acryloyl]-2-methyl-4-(3-piperidin-1- phenyl)-acryloyl]-2-methyl- yl-propyl)-[1,4]diazepan-5-one [1,4]diazepan-5-one (Intermediate 79) 187 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-1-[(E)-3-(3,4-Dichloro- 452.2 acryloyl]-6-methyl-4-(3-piperidin-1- phenyl)-acryloyl]-6-methyl- yl-propyl)-[1,4]diazepan-5-one [1,4]diazepan-5-one (Intermediate 80)

Example 188 1-[(E)-3-(3-Chloro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one

To a suspension of (E)-3-(3-Chloro-phenyl)-acrylic acid acid (26 mg, 0.12 mmol), 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4) (24 mg, 0.1 mmol), O-(7-azabenotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) in DMF (1 ml) was added Et₃N (21 ul, 0.15 mmol) and the mixture shaken for 1 h. The reaction was then directly purified by preparative HPLC affording the title product (28 mg, 69%) as a white powder. MS: 404.2 (MH⁺).

Examples 189-224 General Procedure for Examples 189-224

A solution of 3-{4-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propionaldehyde (intermediate 59) (0.1 mmol) in DCE (0.5 ml) was added to the appropriate amine (0.1 mmol), which are either commercially available or are described in the intermediate section, followed by a freshly prepared solution of pyridine-borane complex (25 ul, 8M in pyridine, 0.2 mmol) and acetic acid (25 ul) in EtOH (0.5 ml). The reaction was then shaken overnight, concentrated and the residue purified by preparative HPLC.

Example MS: No. Compound Name Amine (MH⁺) 189 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- (−)-6-Aza- 464.4 acryloyl]-4-[3-((−)-4-hydroxy-6-aza- Spiro[2.5]octan-4-ol spiro[2.5]oct-6-yl)-propyl]- (intermediate 83) [1,4]diazepan-5-one 190 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- (3S,4S))-4-Methyl- 452.4 acryloyl]-4-[3-((+, cis)-3-hydroxy-4- piperidin-3-ol methyl-piperidin-1-yl)-propyl]- (intermediate 85) [1,4]diazepan-5-one 191 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- (−,cis)-4-Methyl- 452.4 acryloyl]-4-[3-((−, cis)-3-hydroxy-4- piperidin-3-ol methyl-piperidin-1-yl)-propyl]- (intermediate 86) [1,4]diazepan-5-one 192 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- (+)-6-Aza- 464.4 acryloyl]-4-[3-((+)-4-hydroxy-6-aza- spiro[2.5]octan-4-ol spiro[2.5]oct-6-yl)-propyl]- (intermediate 82) [1,4]diazepan-5-one 193 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- (R)-piperidin-3-ol 438.2 acryloyl]-4-[3-((R)-3-hydroxy- piperidin-1-yl)-propyl]-[1,4]diazepan-5- one 194 8-(3-{4-[(E)-3-(3-Chloro-4-fluoro- 1,3,8-Triaza- 506.2 phenyl)-acryloyl]-7-oxo-[1,4]diazepan1- spiro[4.5]decane-2,4- yl}-propyl)-1,3,8-triazaspiro[4.5]decane- dione (intermediate 11) 2,4-dione 195 8-(3-{4-[(E)-3-(3-Chloro-4-fluoro- 2,8-Diaza- 493.2 phenyl)-acryloyl]-7-oxo-[1,4]diazepan1- spiro[4.5]decan-1-one yl}-propyl)-1-oxa-3,8- (intermediate 14) diazaspiro[4.5]decan-2-one 196 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- piperidin-4-ol 438.2 acryloyl]-4-[3-(4-hydroxy-piperidin-1- yl)-propyl]-[1,4]diazepan-5-one 197 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- Tetrahydro-pyran-4- 438.2 acryloyl]-4-[3-(tetrahydro-pyran-4- ylamine ylamino)-propyl]-[1,4]diazepan-5-one 198 8-(3-{4-[(E)-3-(3-Chloro-4-fluoro- 2,8-Diaza- 491.2 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- spiro[4.5]decan-3-one 1-yl}-propyl)-2,8-diaza-spiro[4.5]decan- (intermediate 18) 3-one 199 1-(3-{4-[(E)-3-(3-Chloro-4-fluoro- Piperidine-4-carbonitrile 447.2 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- 1-yl}-propyl)-piperidine-4-carbonitrile 200 N-[1-(3-{4-[(E)-3-(3-Chloro-4-fluoro- N-Piperidin-4-yl- 515.2 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- methanesulfonamide 1-yl}-propyl)-piperidin-4-yl]- (intermediate 29) methanesulfonamide 201 [1-(3-{4-[(E)-3-(3-Chloro-4-fluoro- Piperidin-4-yl-carbamic 495.2 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- acid methyl ester 1-yl}-propyl)-piperidin-4-yl]-carbamic (intermediate 38) acid methyl ester 202 Ethyl-carbamic acid 1-(3-{4-[(E)-3-(3- Ethyl-carbamic acid 509.2 chloro-4-fluoro-phenyl)-acryloyl]-7- piperidin-4-yl oxo-[1,4]diazepan-1-yl}-propyl)- ester (intermediate 41) piperidin-4-yl ester 203 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- 4-(5-Methyl- 504.2 acryloyl]-4-{3-[4-(3-methyl- [1,3,4]oxadiazol-2-yl)- [1,2,4]oxadiazol-5-yl)-piperidin-1-yl]- piperidine (intermediate propyl}-[1,4]diazepan-5-one 42) 204 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- 4-(5-Methyl- 504.2 acryloyl]-4-{3-[4-(5-methyl- [1,3,4]oxadiazol-2-yl)- [1,3,4]oxadiazol-2-yl)-piperidin-1-yl]- piperidine (intermediate propyl}-[1,4]diazepan-5-one 43) 205 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac)-3-methyl- 452.2 phenyl)-acryloyl]-4-[3-(3-hydroxy-3- piperidin-3-ol methyl-piperidin-1-yl)-propyl]- (intermediate 101) [1,4]diazepan-5-one 206 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- 4-dimethylamino- 465.2 acryloyl]-4-[3-(4-dimethylamino- piperidine piperidin-1-yl)-propyl]-[1,4]diazepan-5- one 207 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- 4-(2H-[1,2,4]Triazol-1- 489.2 acryloyl]-4-[3-(4-[1,2,4]triazol-1-yl)- yl)-piperidine piperidin-1-yl)-propyl]-[1,4]diazepan-5- (intermediate 28) one 208 (rac,trans)-1-[(E)-3-(3-Chloro-4- (rac,trans)-2-Methyl- 452.2 fluoro-phenyl)-acryloyl]-4-[3-(3- piperidin-3-ol hydroxy-2-methyl-piperidin-1-yl)- (intermediate 87) propyl]-[1,4]diazepan-5-one 209 (rac,cis)-1-[(E)-3-(3-Chloro-4-fluoro- (rac,cis)-2-Methyl- 452.2 phenyl)-acryloyl]-4-[3-(3-hydroxy-2- piperidin-3-ol methyl-piperidin-1-yl)-propyl]- (intermediate 88) [1,4]diazepan-5-one 210 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac)-2-hydroxymethyl- 452.2 phenyl)-acryloyl]-4-[3-(2- piperidine hydroxymethyl-piperidin-1-yl)-propyl]- [1,4]diazepan-5-one 211 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac)-3-hydroxymethyl- 452.2 phenyl)-acryloyl]-4-[3-(3- piperidine hydroxymethyl-piperidin-1-yl)-propyl]- [1,4]diazepan-5-one 212 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- 4-hydroxymethyl- 452.2 acryloyl]-4-[3-(4-hydroxymethyl- piperidine piperidin-1-yl)-propyl]-[1,4]diazepan-5- one 213 (rac,trans)-1-[(E)-3-(3-Chloro-4- (rac,trans)-4-Fluoro- 456.2 fluoro-phenyl)-acryloyl]-4-[3-(4-fluoro- piperidin-3-ol 3-hydroxy-piperidin-1-yl)-propyl]- (intermediate 89) [1,4]diazepan-5-one 214 (rac,trans)-1-[(E)-3-(3-Chloro-4- (rac,trans)-3-Fluoro- 456.2 fluoro-phenyl)-acryloyl]-4-[3-(3-fluoro- piperidin-4-ol 4-hydroxy-piperidin-1-yl)-propyl]- (intermediate 90) [1,4]diazepan-5-one 215 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac,cis)-4- 468.3 phenyl)-acryloyl]-4-[3-(cis-3-hydroxy-4- hydroxymethyl- hydroxymethyl-piperidin-1-yl)-propyl]- piperidin-3-ol [1,4]diazepan-5-one (intermediate 47) 216 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac,cis)-4- 482.3 phenyl)-acryloyl]-4-[3-(cis-3-hydroxy-4- methoxymethyl methoxymethyl-piperidin-1-yl)-propyl]- piperidin-3-ol [1,4]diazepan-5-one (intermediate 49) 217 (rac)-1-[(E)-3-(3-Chloro-fluoro- (rac,trans)-4- 468.3 phenyl)-acryloyl]-4-[3-(trans-3- hydroxymethyl hydroxy-4-hydroxymethyl-piperidin-1- piperidin-3-ol yl)-propyl]-[1,4]diazepan-5-one (intermediate 48) 218 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac,cis)-3-methoxy- 482.3 phenyl)-acryloyl]-4-[3-(cis-3-methoxy- piperidin-4-yl-methanol 4-hydroxymethyl-piperidin-1-yl)- (intermediate 50) propyl]-[1,4]diazepan-5-one 219 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac,cis)-4- 482.4 phenyl)-acryloyl]-4-[3-(cis-3-hydroxy-4- hydroxymethyl-4- hydroxymethyl-4-methyl-piperidin-1yl)- methyl-piperidin-3-ol propyl]-[1,4]diazepan-5-one (intermediate 52) 220 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac,trans)-4- 482.3 phenyl)-acryloyl]-4-[3-(trans-3- hydroxymethyl-4- hydroxy-4-hydroxymethyl-4-methyl- methyl-piperidin-3-ol piperidin-1-yl)-propyl]-[1,4]diazepan-5- (intermediate 53) one 221 (rac)-1-[(E)-3-(3-Chloro-fluoro- (rac)-6-methyl- 452.3 phenyl)-acryloyl]-4-[3-(5-hydroxy-2- piperidin-3-ol methyl-piperidin-1-yl)-propyl]- (intermediate 66) [1,4]diazepan-5-one 222 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac)-6-hydroxymethyl- 468.3 phenyl)-acryloyl]-4-[3-(5-hydroxy-2- piperidin-2-ol hydroxymethyl-piperidin-1-yl)-propyl]- (intermediate 65) [1,4]diazepan-5-one 223 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac)-4,4-dimethyl- 466.3 phenyl)-acryloyl]-4-[3-(3-hydroxy-4,4- piperidin-3-ol dimethyl-piperidin-1-yl)-propyl]- (intermediate 84) [1,4]diazepan-5-one 224 (rac,cis)-1-[(E)-3-(3-Chloro-4-fluoro- (rac,cis)-5-methyl- 452.3 phenyl)-acryloyl]-4-[3-(3-hydroxy-5- piperidin-3-ol methyl-piperidin-1-yl)-propyl]- (intermediate 75) [1,4]diazepan-5-one

Examples 225-279 General Procedure for Examples 225-279

A solution of 3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propionaldehyde (intermediate 2) (0.1 mmol) in DCE (0.5 ml) was added to the appropriate amine (0.1 mmol) which are either commercially available or are described in the intermediate section, followed by a freshly prepared solution of pyridine-borane complex (25 ul, 8M in pyridine, 0.2 mmol) and acetic acid (25 ul) in EtOH (0.5 ml). The reaction was then shaken overnight, concentrated and the residue purified by preparative HPLC.

Example MS: No. Compound Name Amine (MH⁺) 225 (rac,trans)-1-[(E)-3-(3,4- (rac,trans)-2-methyl- 468.2 Dichlorophenyl)-acryloyl]-4-[3-(3- piperidin-3-ol hydroxy-2-methyl-piperidin-1-yl)- (intermediate 87) propyl]-[1,4]diazepan-5-one 226 (rac,cis)-1-[(E)-3-(3,4-Dichloro- (rac, cis)-2-methyl- 468.2 phenyl)-acryloyl]-4-[3-(3-hydroxy-2- piperidin-3-ol methyl-piperidin-1-yl)-propyl]- (intermediate 88) [1,4]diazepan-5-one 227 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-2-hydroxymethyl- 468.2 acryloyl]-4-[3-(2-hydroxymethyl- piperidine piperidin-1-yl)-propyl]-[1,4]diazepan-5- one 228 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-hydroxymethyl- 468.2 acryloyl]-4-[3-(3-hydroxymethyl- piperidine piperidin-1-yl)-propyl]-[1,4]diazepan-5- one 229 1-[(E)-3-(3,4-Dichloro-phenyl)- 4-hydroxymethyl- 468.2 acryloyl]-4-[3-(4-hydroxymethyl- piperidine piperidin-1-yl)-propyl]-[1,4]diazepan-5- one 230 (rac,trans)-1-[(E)-3-(3,4-Dichloro- (rac,trans)-4-Fluoro- 472.2 phenyl)-acryloyl]-4-[3-(4-fluoro-3- piperidin-3-ol hydroxy-piperidin-1-yl)-propyl]- (intermediate 89) [1,4]diazepan-5-one 231 (rac,trans)-1-[(E)-3-(3,4-Dichloro- (rac,trans)-3-Fluoro- 472.2 phenyl)-acryloyl]-4-[3-(3-fluoro-4- piperidin-4-ol hydroxy-piperidin-1-yl)-propyl]- (intermediate 90) [1,4]diazepan-5-one 232 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methyl- 468.2 acryloyl]-4-[3-(3-hydroxy-3-methyl- piperidin-3-ol piperidin-1-yl)-propyl]-[1,4]diazepan-5- (intermediate 101) one 233 (rac, cis)-1-[(E)-3-(3,4-Dichloro- (rac, cis)-3-Fluoro- 472.3 phenyl)-acryloyl]-4-[3-(3-fluoro-4- piperidin-4-ol hydroxy-piperidin-1-yl)-propyl]- (intermediate 93) [1,4]diazepan-5-one 234 1-[(E)-3-(3,4-Dichloro-phenyl)- 1-(2-Methoxy-ethyl)- 497.3 acryloyl]-4-{3-[4-(2-methoxy-ethyl)- piperazine piperazin-1-yl]-propyl}-[1,4]diazepan-5- one 235 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methyl- 452.3 acryloyl]-4-[3-(3-methyl-piperidin-1- piperidine yl)-propyl]-[1,4]diazepan-5-one 236 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methoxymethyl- 482.3 acryloyl]-4-[3-(3-methoxymethyl- piperidine piperidin-1-yl)-propyl]-[1,4]diazepan-5- one 237 1-[(E)-3-(3,4-Dichloro-phenyl)- Piperazin-2-one 453.3 acryloyl]-4-[3-(3-oxo-piperazin-1-yl)- propyl]-[1,4]diazepan-5-one 238 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-4-methyl- 468.3 acryloyl]-4-[3-(3-hydroxy-4-methyl- piperidin-3-ol piperidin-1-yl)-propyl]-[1,4]diazepan-5- (intermediate 91) one 239 1-[(E)-3-(3,4-Dichloro-phenyl)- [1,4]Diazepan-5-one 467.2 acryloyl]-4-[3-(5-oxo-[1,4]diazepan-1- yl)-propyl]-[1,4]diazepan-5-one 240 1-[(E)-3-(3,4-Dichloro-phenyl)- 1-Isopropyl-piperazine 481.3 acryloyl]-4-[3-(4-isopropyl-piperazin-1- yl)-propyl]-[1,4]diazepan-5-one 241 1-[(E)-3-(3,4-Dichloro-phenyl)- 1-Cyclopropyl- 479.3 acryloyl]-4-[3-(4-cyclopropyl-piperazin- piperazine 1-yl)-propyl]-[1,4]diazepan-5-one 242 1-[(E)-3-(3,4-Dichloro-phenyl)- 1-Cyclopentyl-piperazine 507.3 acryloyl]-4-[3-(4-cyclopentyl-piperazin- 1-yl)-propyl]-[1,4]diazepan-5-one 243 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methyl- 468.3 acryloyl]-4-[3-(4-hydroxy-3-methyl- piperidin-4-ol piperidin-1-yl)-propyl]-[1,4]diazepan-5- (intermediate 94) one 244 [1-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)- Piperidin-4-yl-carbamic 511.3 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- acid methyl propyl)-piperidin-4-yl]-carbamic acid ester (intermediate 38) methyl ester 245 [1-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)- Methyl-piperidin-4-yl- 525.3 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- carbamic acid methyl propyl)-piperidin-4-yl]-methyl-carbamic ester (intermediate 39) acid methyl ester 246 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-1-Isopropyl-2- 495.7 acryloyl]-4-[3-(4-isopropyl-3-methyl- methyl-piperazine piperazin-1-yl)-propyl]-[1,4]diazepan-5- one 247 1-[(E)-3-(3,4-Dichloro-phenyl)- 4-methoxymethyl- 482.3 acryloyl]-4-[3-(4-methoxymethyl- piperidine piperidin-1-yl)-propyl]-[1,4]diazepan-5- one 248 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-(3-methyl- 482.3 acryloyl]-4-[3-(3-hydroxymethyl-3- piperidin-3-yl) methanol methyl-piperidin-1-yl)-propyl]- (intermediate 30) [1,4]diazepan-5-one 249 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methoxymethyl- 496.3 acryloyl]-4-[3-(3-methoxymethyl-3- 3-methyl-piperidine methyl-piperidin-1-yl)-propyl]- (intermediate 31) [1,4]diazepan-5-one 250 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-(2-methyl- 482.3 acryloyl]-4-[3-(2-hydroxymethyl-2- piperidin-2-yl) methanol methyl-piperidin-1-yl)-propyl]- (intermediate 34) [1,4]diazepan-5-one 251 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-6-Aza- 480.3 acryloyl]-4-[3-(4-hydroxy-6-aza- spiro[2.5]octan-4-ol spiro[2.5]oct-6-yl)-propyl]- (intermediate 81) [1,4]diazepan-5-one 252 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-5-Aza- 480.3 acryloyl]-4-[3-(8-hydroxy-5-aza- spiro[2.5]octan-8-ol spiro[2.5]oct-5-yl)-propyl]- (intermediate 98) [1,4]diazepan-5-one 253 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac, cis)-3-methyl- 468.3 acryloyl]-4-[3-(cis-4-hydroxy-3-methyl- piperidin-4-ol piperidin-1-yl)-propyl]-[1,4]diazepan-5- (intermediate 96) one 254 1-[(E)-3-(3,4-Dichloro-phenyl)- (4-methyl-piperidin-4- 482.3 acryloyl]-4-[3-(4-hydroxymethyl-4- yl) methanol methyl-piperidin-1-yl)-propyl]- (intermediate 32) [1,4]diazepan-5-one 255 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-2-hydroxymethyl- 468.3 acryloyl]-4-[3-(2-hydroxymethyl-2- 2-methyl-pyrrolidine methyl-pyrrolidin-1-yl)-propyl]- [1,4]diazepan-5-one 256 (rac)-[1-(3-{4-[(E)-3-(3,4-Dichloro- (rac)-Piperidin-3-yl- 511.3 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- carbamic acid methyl 1-yl}-propyl)-piperidin-3-yl]- ester (intermediate 40) carbamicacid methyl ester 257 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3,3-dimethyl- 482.4 acryloyl]-4-[3-(4-hydroxy-3,3-dimethyl- piperidin-4-ol piperidin-1-yl)-propyl]-[1,4]diazepan-5- (intermediate 97) one 258 1-[(E)-3-(3,4-Dichloro-phenyl)- 1-Isobutyl-piperazine 495.4 acryloyl]-4-[3-(4-isobutyl-piperazin-1- yl)-propyl]-[1,4]diazepan-5-one 259 1-[(E)-3-(3,4-Dichloro-phenyl)- (+,cis)-4-Methyl- 468.3 acryloyl]-4-[3-((+, cis)-3-hydroxy-4- piperidin-3-ol methyl-piperidin-1-yl)-propyl]- (intermediate 85) [1,4]diazepan-5-one 260 1-[(E)-3-(3,4-Dichloro-phenyl)- (−,cis)-4-Methyl- 468.3 acryloyl]-4-[3-((−, cis)-3-hydroxy-4- piperidin-3-ol methyl-piperidin-1-yl)-propyl]- (intermediate 86) [1,4]diazepan-5-one 261 1-[(E)-3-(3,4-Dichloro-phenyl)- (+)-6-Aza- 480.3 acryloyl]-4-[3-((+)-4-hydroxy-6-aza- spiro[2.5]octan-4-ol spiro[2.5]oct-6-yl)-propyl]- (intermediate 82) [1,4]diazepan-5-one 262 1-[(E)-3-(3,4-Dichloro-phenyl)- (−)-6-Aza- 480.3 acryloyl]-4-[3-((−)-4-hydroxy-6-aza- spiro[2.5]octan-4-ol spiro[2.5]oct-6-yl)-propyl]- (intermediate 83) [1,4]diazepan-5-one 263 (rac)-4-(3-{4-[(E)-3-(3,4-Dichloro- (rac)-Piperazine-2- 497.3 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- carboxylic acid methyl 1-yl}-propyl)-piperazine-2-carboxylic ester acid methyl ester 264 1-[(E)-3-(3,4-Dichloro-phenyl)- 1-Methyl-piperazin-2- 467.3 acryloyl]-4-[3-(4-methyl-3-oxo- one piperazin-1-yl)-propyl]-[1,4]diazepan-5- one 265 (rac)-(3-{4-[(E)-3-(3,4-Dichloro- (rac)-1-Oxa-4,9-diaza- 523.4 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- spiro[5.5]undecan-3- 1-yl}-propyl)-1-oxa-4,9-diaza- one (intermediate 102) spiro[5.5]undecan-3-one 266 (rac,cis)-1-[(E)-3-(3,4-Dichloro- (rac,cis)-4- 484.3 phenyl)-acryloyl]-4-[3-(3-hydroxy-4- hydroxymethyl- hydroxymethyl-piperidin-1-yl)-propyl]- piperidin-3-ol [1,4]diazepan-5-one (intermediate 47) 267 (rac,cis)-1-[(E)-3-(3,4-Dichloro- (rac,cis)-4- 498.3 phenyl)-acryloyl]-4-[3-(3-hydroxy-4- methoxymethyl- methoxymethyl-piperidin-1-yl)-propyl]- piperidin-3-ol [1,4]diazepan-5-one (intermediate 49) 268 (rac,trans)-1-[(E)-3-(3,4-Dichloro- (rac,trans)-4- 484.3 phenyl)-acryloyl]-4-[3-(3-hydroxy-4- hydroxymethyl- hydroxymethyl-piperidin-1-yl)-propyl]- piperidin-3-ol [1,4]diazepan-5-one (intermediate 48) 269 (rac,cis)-1-[(E)-3-(3,4-Dichloro- (rac,cis)-3- 498.3 phenyl)-acryloyl]-4-[3-(3-methoxy-4- methoxymethyl- hydroxymethyl-piperidin-1-yl)-propyl]- piperidin-4-ol [1,4]diazepan-5-one (intermediate 50) 270 (rac,cis)-1-[(E)-3-(3,4-Dichloro- (rac,cis)-4- 498.3 phenyl)-acryloyl]-4-[3-(3-hydroxy-4- hydroxymethyl-4- hydroxymethyl-4-methyl-piperidin-1- methyl-piperidin-3-ol yl)-propyl]-[1,4]diazepan-5-one (intermediate 52) 271 (rac,trans)-1-[(E)-3-(3,4-Dichloro- (rac,trans)-4- 498.3 phenyl)-acryloyl]-4-[3-(3-hydroxy-4- hydroxymethyl-4- hydroxymethyl-4-methyl-piperidin-1- methyl-piperidin-3-ol yl)-propyl]-[1,4]diazepan-5-one (intermediate 53) 272 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-6-methyl- 468.3 acryloyl]-4-[3-(5-hydroxy-2-methyl- piperidin-3-ol piperidin-1-yl)-propyl]-[1,4]diazepan-5- (intermediate 66) one 273 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-6-hydroxymethyl- 484.3 acryloyl]-4-[3-(5-hydroxy-2- piperidin-3-ol hydroxymethyl-piperidin-1-yl)-propyl]- (intermediate 65) [1,4]diazepan-5-one 274 (rac)-1-[(E)3-(3,4-Dichloro-phenyl)- (rac)-4,4-dimethyl- 482.3 acryloyl]-4-[3-(3-hydroxy-4,4-dimethyl- piperidin-3-ol piperidin-1-yl)-propyl]-[1,4]diazepan-5- (intermediate 97) one 275 (rac,cis)-1-[(E)-3-(3,4-Dichloro- (rac,cis)-3-Methoxy- 484.2 phenyl)-acryloyl]-4-[3-(3-methoxy- tetrahydro-pyran-4- tetrahydro-pyran-4-ylamino)-propyl]- ylamine (intermediate [1,4]diazepan-5-one 20) 276 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-dimethylamino- 481.2 acryloyl]-4-[3-(3-dimethylamino- piperidine piperidin-1-yl)-propyl]-[1,4]diazepan-5- one 277 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-dimethylamino- 467.2 acryloyl]-4-[3-(3-dimethylamino- pyrollidine pyrollidin-1-yl)-propyl]-[1,4]diazepan- 5-one 278 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-diethylamino- 495.2 acryloyl]-4-[3-(3-diethylamino- pyrollidine pyrollidin-1-yl)-propyl]-[1,4]diazepan- 5-one 279 (rac,cis)-1-[(E)-3-(3,4-Dichloro- (rac,cis)-5-methyl- 468.3 phenyl)-acryloyl]-4-[3-(3-hydroxy-5- piperidin-3-ol methyl-piperidin-1-yl)-propyl]- (intermediate 75) [1,4]diazepan-5-one

Examples 280-326 General Procedure for Examples 280-326

A solution of (rac)-1-[(E)-3-(3, 4-Dichloro-phenyl)-acryloyl]-4-oxiranylmethyl-[1,4]diazepan-5-one (example 166A) (0.1 mmol) in DMA (0.5 ml) was added to the appropriate amine (0.15 mmol), which are either commercially available or are described in the intermediate section, and a generous spatula of cesium carbonate added. The reaction was then shaken overnight at 80° C., filtered, and directly purifed purified by preparative HPLC.

Example MS: No. Compound Name Amine (MH⁺) 280 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-4-methyl- 484.3 acryloyl]-4-[2-hydroxy-3-(3-hydroxy-4- piperidin-3-ol methyl-piperidin-1-yl)-propyl]- (intermediate 91) [1,4]diazepan-5-one 281 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3- 470.2 acryloyl]-4-[2-hydroxy-3-(3-hydroxy- hydroxypiperidine piperidin-1-yl)-propyl]-[1,4]diazepan-5- one 282 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-2-methyl- 484.3 acryloyl]-4-[2-hydroxy-3-((trans)-3- piperidin-3-ol hydroxy-2-methyl-piperidin-1-yl)- (intermediate 87) propyl]-[1,4]diazepan-5-one 283 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3- 484.3 acryloyl]-4-[2-hydroxy-3-(3-methoxy- methoxypiperidine piperidin-1-yl)-propyl]-[1,4]diazepan-5- one 284 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-4-Fluoro- 488.2 acryloyl]-4-[3-(trans-4-fluoro-3- piperidin-3-ol hydroxy-piperidin-1-yl)-2-hydroxy- (intermediate 89) propyl]-[1,4]diazepan-5-one 285 1-[(E)-3-(3,4-Dichloro-phenyl)- Piperidin-4-ol 470.2 acryloyl]-4-[2-hydroxy-3-(4-hydroxy- piperidin-1-yl)-propyl]-[1,4]diazepan-5- one 286 (rac)1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-3-fluoro- 488.3 acryloyl]-4-[3-(trans-3-fluoro-4- piperidin-4-ol hydroxy-piperidin-1-yl)-2-hydroxy- (intermediate 90) propyl]-[1,4]diazepan-5-one 287 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac, cis)-3-fluoro- 488.2 acryloyl]-4-[3-(cis-4-fluoro-3-hydroxy- piperidin-4-ol piperidin-1-yl)-2-hydroxy-propyl]- (intermediate 93) [1,4]diazepan-5-one 288 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methylpiperidine 468.3 acryloyl]-4-[2-hydroxy-3-(3-methyl- piperidin-1-yl)-propyl]-[1,4]diazepan-5- one 289 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-hydroxymethyl- 484.3 acryloyl]-4-[2-hydroxy-3-(3- piperidine hydroxymethyl-piperidin-1-yl)-propyl]- [1,4]diazepan-5-one 290 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-2-hydroxymethyl- 484.3 acryloyl]-4-[2-hydroxy-3-(2- piperidine hydroxymethyl-piperidin-1-yl)-propyl]- [1,4]diazepan-5-one 291 (rac)-(1-[(E)-3-(3,4-Dichloro-phenyl)- Piperidin-4-ol 484.3 acryloyl]-4-[2-hydroxy-3-(4- hydroxymethyl-piperidin-1-yl)-propyl]- [1,4]diazepan-5-one 292 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-hydroxy- 456.2 acryloyl]-4-[2-hydroxy-3-(3-hydroxy- pyrrolidine pyrrolidin-1-yl)-propyl]-[1,4]diazepan- 5-one 293 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methoxymethyl- 498.3 acryloyl]-4-[2-hydroxy-3-(3- piperidine methoxymethyl-piperidin-1-yl)-propyl]- [1,4]diazepan-5-one 294 (rac)-[1-(3-{4-[(E)-3-(3,4-Dichloro- Piperidin-4-yl-carbamic 527.3 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- acid methylester 1-yl}-2-hydroxy-propyl)-piperidin-4-yl]- (intermediate 38) carbamic acid methyl ester 295 (rac)-[1-(3-{4-[(E)-3-(3,4-Dichloro- Methyl-piperidin-4-yl- 541.3 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- carbamic acid methyl 1-yl}-2-hydroxy-propyl)-piperidin-4-yl]- ester (intermediate 39) methyl-carbamic acid methyl ester 296 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- 1-Isopropyl-piperazine 497.4 acryloyl]-4-[2-hydroxy-3-(4-isopropyl- piperazin-1-yl)-propyl]-[1,4]diazepan-5- one 297 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- 1-Cyclopropyl- 495.3 acryloyl]-4-[3-(4-cyclopropyl-piperazin- piperazine 1-yl)-2-hydroxy-propyl]-[1,4]diazepan- 5-one 298 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- 1-Cyclopentyl-piperazine 523.4 acryloyl]-4-[3-(4-cyclopentyl-piperazin- 1-yl)-2-hydroxy-propyl]-[1,4]diazepan- 5-one 299 (rac)-1[(E)-3-(3,4-Dichloro-phenyl)- 1-(2-Methoxy-ethyl)- 513.4 acryloyl]-4-{2-hydroxy-3-[4-(2- piperazine methoxy-ethyl)-piperazin-1-yl]-propyl}- [1,4]diazepan-5-one 300 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methyl- 484.3 acryloyl]-4-[2-hydroxy-3-(4-hydroxy-3- piperidin-4-ol methyl-piperidin-1-yl)-propyl]- (intermediate 94) [1,4]diazepan-5-one 301 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-1-Isopropyl-2- 511.3 acryloyl]-4-[2-hydroxy-3-(4-isopropyl- methyl-piperazine 3-methyl-piperazin-1-yl)-propyl]- [1,4]diazepan-5-one 302 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- 1-Methyl-piperazine 469.3 acryloyl]-4-[2-hydroxy-3-(4-methyl- piperazin-1-yl)-propyl]-[1,4]diazepan-5- one 303 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methyl- 484.3 acryloyl]-4-[2-hydroxy-3-(3-hydroxy-3- piperidin-3-ol methyl-piperidin-1-yl)-propyl]- (intermediate 101) [1,4]diazepan-5-one 304 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- 4-methoxymethyl- 498.3 acryloyl]-4-[2-hydroxy-3-(4- piperidine methoxymethyl-piperidin-1-yl)-propyl]- [1,4]diazepan-5-one 305 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-(3-methyl- 498.3 acryloyl]-4-[2-hydroxy-3-(3- piperidin-3-yl) methanol hydroxymethyl-3-methyl-piperidin-1- (intermediate 30) yl)-propyl]-[1,4]diazepan-5-one 306 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methoxymethyl- 512.3 acryloyl]-4-[2-hydroxy-3-(3- 3-methyl-piperidine methoxymethyl-3-methyl-piperidin-1- (intermediate 31) yl)-propyl]-[1,4]diazepan-5-one 307 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-(2-methyl- 498.3 acryloyl]-4-[2-hydroxy-3-(2-hydroxy-2- piperidin-2-yl) methanol hydroxymethyl-piperidin-1-yl)-propyl]- (intermediate 34) [1,4]diazepan-5-one 308 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,cis)-2- 500.3 acryloyl]-4-[2-hydroxy-3-(cis-4- hydroxymethyl- hydroxy-2-hydroxymethyl-piperidin-1- piperidin-4-ol yl)-propyl]-[1,4]diazepan-5-one (intermediate 45) 309 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-6-Aza- 496.5 acryloyl]-4-[2-hydroxy-3-(4-hydroxy-6- spiro[2.5]octan-4-ol aza-spiro[2.5]oct-6-yl)-propyl]- (intermediate 81) [1,4]diazepan-5-one 310 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-hydroxymethyl- 500.5 acryloyl]-4-[2-hydroxy-3-(4-hydroxy-3- piperidin-4-ol hydroxymethyl-piperidin-1-yl)-propyl]- (intermediate 35) [1,4]diazepan-5-one 311 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methoxymethyl- 514.5 acryloyl]-4-[2-hydroxy-3-(4-hydroxy-3- piperidin-4-ol methoxymethyl-piperidin-1-yl)-propyl]- (intermediate 35) [1,4]diazepan-5-one 312 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-4-methoxy-3- 528.5 acryloyl]-4-[2-hydroxy-3-(4-methoxy-3- methoxymethyl- methoxymethyl-piperidin-1-yl)-propyl]- piperidine (intermediate [1,4]diazepan-5-one 37) 313 (rac)1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-2- 500.5 acryloyl]-4-[2-hydroxy-3-(trans-4- hydroxymethyl- hydroxy-2-hydroxymethyl-piperidin-1- piperidin-4-ol yl)-propyl]-[1,4]diazepan-5-one (intermediate 46) 314 (rac)-N-[1-(3-{4-[(E)-3-(3,4-Dichloro- N-Piperidin-4-yl- 511.5 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- acetamide 1-yl}-2-hydroxy-propyl)-piperidin-4-yl]- acetamide 315 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-4-methyl- 484.5 acryloyl]-4-[2-hydroxy-3-(trans-3- piperidin-3-ol hydroxy-4-methyl-piperidin-1-yl)- (intermediate 100) propyl]-[1,4]diazepan-5-one 316 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-3-methyl- 484.5 acryloyl]-4-[2-hydroxy-3-(trans-4- piperidin-4-ol hydroxy-3-methyl-piperidin-1-yl)- (intermediate 95) propyl]-[1,4]diazepan-5-one 317 (rac)1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-5-Aza- 496.3 acryloyl]-4-[2-hydroxy-3-(8-hydroxy-5- spiro[2.5]octan-8-ol aza-spiro[2.5]oct-5-yl)-propyl]- (intermediate 81) [1,4]diazepan-5-one 318 (rac)-1-[3-(3,4-Dichloro-phenyl)- (rac,cis)-3-methyl- 484.3 acryloyl]-4-[2-hydroxy-3-(cis-4- piperidin-4-ol hydroxy-3-methyl-piperidin-1-yl)- (intermediate 96) propyl]-[1,4]diazepan-5-one 319 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (4-methyl-piperidin-4- 498.3 acryloyl]-4-[2-hydroxy-3-(4- yl) methanol hydroxymethyl-4-methyl-piperidin-1- (intermediate 32) yl)-propyl]-[1,4]diazepan-5-one 320 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- 2-Methylamino-ethanol 444.3 acryloyl]-4-{2-hydroxy-3-[(2-hydroxy- ethyl)-methyl-amino]-propyl}- [1,4]diazepan-5-one 321 (rac)-1-[(E)-3-(3,4-Dichloro-pheny)- 2-Ethylamino-ethanol 458.3 acryloyl]-4-{3-[ethyl-(2-hydroxy-ethyl)- amino]-2-hydroxy-propyl}- [1,4]diazepan-5-one 322 (rac)-1-[3-(3,4-Dichloro-phenyl)- (rac)-2-hydroxymethyl- 484.3 acryloyl]-4-[2-hydroxy-3-(2- 2-methyl-pyrrolidine hydroxymethyl-2-methyl-pyrrolidin-1- yl)-propyl]-[1,4]diazepan-5-one 323 (rac)-[1-(3-{4-[(E)-3-(3,4-Dichloro- (rac)-Piperidin-3-yl- 527.3 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- carbamic acid methyl 1-yl}-2-hydroxy-propyl)-piperidin-3-yl]- ester (intermediate 40) carbamic acid methyl ester 324 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3,3-dimethyl- 498.3 acryloyl]-4-[2-hydroxy-3-(4-hydroxy- piperidin-4-ol 3,3-dimethyl-piperidin-1-yl)-propyl]- (intermediate 97) [1,4]diazepan-5-one 325 (rac)-1-[3-(3,4-Dichloro-phenyl)- 1-Isobutyl-piperazine 511.4 acryloyl]-4-[2-hydroxy-3-(4-isobutyl- piperazin-1-yl)-propyl]-[1,4]diazepan-5- one 326 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- 1-Oxa-8-aza- 510.3 acryloyl]-4-[2-hydroxy-3-(1-oxa-8-aza- spiro[4.5]decane spiro[4.5]dec-8-yl)-propyl]- (intermediate 27) [1,4]diazepan-5-one

Examples 327-335 General Procedure for Examples 327-335

A solution of 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(R)-1-oxiranylmethyl-[1,4]diazepan-5-one (example 167C) (0.1 mmol) in DMA (0.5 ml) was added to the appropriate amine (0.15 mmol), which are either commercially available or are described in the intermediate section, and a generous spatula of cesium carbonate added. The reaction was then shaken overnight at 80° C., filtered, and directly purifed purified by preparative HPLC.

Example MS: No. Compound Name Amine (MH⁺) 327 1-[(E)-3-(3,4-Dichloro-phenyl)- (−)-6-Aza- 496.3 acryloyl]-4-[(S)-2-hydroxy-3-((−)-4- spiro[2.5]octan-4-ol hydroxy-6-aza-spiro[2.5]oct-6-yl)- (intermediate 83) propyl]-[1,4]diazepan-5-one 328 1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,cis)-4- 500.3 acryloyl]-4-[(S)-2-hydroxy-3-(cis-3- hydroxymethyl- hydroxy-4-hydroxymethyl-piperidin-1- piperidin-3-ol yl)-propyl]-[1,4]diazepan-5-one (intermediate 47) 329 1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,cis)-4- 514.3 acryloyl]-4-[(S)-2-hydroxy-3-(cis-3- methoxymethyl- hydroxy-4-methoxymethyl-piperidin-1- piperidin-3-ol yl)-propyl]-[1,4]diazepan-5-one (intermediate 49) 330 1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,cis)-4- 514.3 acryloyl]-4-[(S)-2-hydroxy-3-((cis)-3- hydroxymethyl-4- hydroxy-4-hydroxymethyl-4-methyl- methyl-piperidin-3-ol piperidin-1-yl)-propyl]-[1,4]diazepan-5-one (intermediate 52) 331 1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-4- 514.3 acryloyl]-4-[(S)-2-hydroxy-3-((trans)-3- hydroxymethyl-4- hydroxy-4-hydroxymethyl-4-methyl- methyl-piperidin-3-ol piperidin-1-yl)-propyl]-[1,4]diazepan-5- (intermediate 53) one 332 1-[(E)-3-(3,4-Dichloro-phenyl)- (+)-6-Aza- 496.3 acryloyl]-4-[(S)-2-hydroxy-3-((+)-4- spiro[2.5]octan-4-ol hydroxy-6-aza-spiro[2.5]oct-6-yl)- (intermediate 82) propyl]-[1,4]diazepan-5-one 333 1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-4- 500.3 acryloyl]-4-[(S)-2-hydroxy-3-(trans-3- hydroxymethyl- hydroxy-4-hydroxymethyl-piperidin-1- piperidin-3-ol yl)-propyl]-[1,4]diazepan-5-one (intermediate 48) 334 1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-4,4-dimethyl- 498.3 acryloyl]-4-[(S)-2-hydroxy-3-(3- piperidin-3-ol hydroxy-4,4-dimethyl-piperidin-1-yl)- (intermediate 84) propyl]-[1,4]diazepan-5-one 335 1-[(E)-3-(3,4-Dichloro-phenyl)- (rac, cis)-5-methyl- 484.3 acryloyl]-4-[(S)-2-hydroxy-3-(cis-3- piperidin-3-ol hydroxy-5-methyl-piperidin-1-yl)- (intermediate 75) propyl]-[1,4]diazepan-5-one

Examples 336-344 General Procedure for Examples 336-344

A solution of 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-((R)-2-oxiranyl-ethyl)-[1,4]diazepan-5-one (intermediate 56) (0.1 mmol) in DMA (0.5 ml) was added to the appropriate amine (0.15 mmol), which are either commercially available or are described in the intermediate section, and a generous spatula of cesium carbonate added. The reaction was then shaken overnight at 80° C., filtered, and directly purifed purified by preparative HPLC.

Example MS: No. Compound Name Amine (MH⁺) 336 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- (−)-6-Aza- 480.3 acryloyl]-4-[(S)-2-hydroxy-3-((−)-4- spiro[2.5]octan-4-ol hydroxy-6-aza-spiro[2.5]oct-6-yl)- (intermediate 83) propyl]-[1,4]diazepan-5-one 337 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- (rac,cis)-4- 484.3 acryloyl]-4-[(S)-2-hydroxy-3-(cis-3- hydroxymethyl- hydroxy-4-hydroxymethyl-piperidin-1- piperidin-3-ol yl)-propyl]-[1,4]diazepan-5-one (intermediate 47) 338 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- (rac,cis)-4- 498.3 acryloyl]-4-[(S)-2-hydroxy-3-(cis-3- methoxymethyl- hydroxy-4-methoxymethyl-piperidin-1- piperidin-3-ol yl)-propyl]-[1,4]diazepan-5-one (intermediate 49) 339 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- (rac,trans)-4- 484.3 acryloyl]-4-[(S)-2-hydroxy-3-(trans-3- hydroxymethyl- hydroxy-4-hydroxymethyl-piperidin-1- piperidin-3-ol yl)-propyl]-[1,4]diazepan-5-one (intermediate 48) 340 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- (rac,cis)-4- 498.3 acryloyl]-4-[(S)-2-hydroxy-3-((cis)-3- hydroxymethyl-4- hydroxy-4-hydroxymethyl-4-methyl- methyl-piperidin-3-ol piperidin-1-yl)-propyl]-[1,4]diazepan-5-one (intermediate 52) 341 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- (rac,trans)-4- 498.3 acryloyl]-4-[(S)-2-hydroxy-3-((trans)-3- hydroxymethyl-4- hydroxy-4-hydroxymethyl-4-methyl- methyl-piperidine-3-ol piperidin-1-yl)-propyl]-[1,4]diazepan-5- (intermediate 53) one 342 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- (+)-6-Aza- 480.3 acryloyl]-4-[(S)-2-hydroxy-3-((+)-4- Spiro[2.5]octan-4-ol hydroxy-6-aza-spiro[2.5]oct-6-yl)- (intermediate 82) propyl]-[1,4]diazepan-5-one 343 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- (rac)-4,4-dimethyl- 482.3 acryloyl]-4-[(S)-2-hydroxy-3-(3- piperidin-3-ol hydroxy-4,4-dimethyl-piperidin-1-yl)- (intermediate 84) propyl]-[1,4]diazepan-5-one 344 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- (rac,cis)-5-methyl- 468.3 acryloyl]-4-[(S)-2-hydroxy-3-(cis-3- piperidin-3-ol hydroxy-5-methyl-piperidin-1-yl)- (intermediate 75) propyl]-[1,4]diazepan-5-one

Examples 345-357 General Procedure for Examples 345-357

A solution of 3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-acetaldehyde (intermediate 3) (0.1 mmol) in DCE (0.5 ml) was added to the appropriate amine (0.1 mmol), which are either commercially available or are described in the intermediate section, followed by a freshly prepared solution of pyridine-borane complex (25 ul, 8M in pyridine, 0.2 mmol) and acetic acid (25 ul) in EtOH (0.5 ml). The reaction was then shaken overnight, concentrated and the residue purified by preparative HPLC.

Example MS: No. Compound Name Amine (MH⁺) 345 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-dimethylamino- 469.2 acryloyl]-4-[2-(3-dimethylamino- piperidine piperidin-1-yl)-ethyl]-[1,4]diazepan-5- one 346 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-dimethylamino- 453.2 acryloyl]-4-[2-(3-dimethylamino- pyrollidine pyrollidin-1-yl)-ethyl]-[1,4]diazepan-5- one 347 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-diethylamino- 481.2 acryloyl]-4-[2-(3-diethylamino- pyrollidine pyrollidin-1-yl)-ethyl]-[1,4]diazepan-5- one 348 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-2-methyl- 424.3 acryloyl]-4-[2-(2-methyl-pyrrolidin-1- pyrrolidine yl)-ethyl]-[1,4]diazepan-5-one 349 (rac)1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-2,5-dimethyl- 438.3 acryloyl]-4-[2-(trans-2,5-dimethyl- pyrrolidine pyrrolidin-1-yl)-ethyl]-[1,4]diazepan-5-one 350 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-2-hydroxymethyl- 454.3 acryloyl]-4-[2-(2-hydroxymethyl-2- 2-methyl-pyrrolidine methyl-pyrrolidin-1-yl)-ethyl]- [1,4]diazepan-5-one 351 (rac)-[1-(2-{4-[(E)-3-(3,4-Dichloro- (rac)-Piperidin-3-yl- 497.3 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- carbamic acid methyl 1-yl}-ethyl)-piperidin-3-yl]-carbamic ester (intermediate 40) acid methyl ester 352 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3,3-dimethyl- 468.3 acryloyl]-4-[2 -(4-hydroxy-3,3-dimethyl- piperidin-4-ol piperidin-1-yl)-ethyl]-[1,4]diazepan-5- (intermediate 97) one 353 1-[(E)-3-(3,4-Dichloro-phenyl)- 1-Isobutyl-piperazine 481.3 acryloyl]-4-[2-(4-isobutyl-piperazin-1- yl)-ethyl]-[1,4]diazepan-5-one 354 (rac)-N-[1-(2-{4-[(E)-3-(3,4-Dichloro- (rac)-N-Piperidin-3-yl- 481.3 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- acetamide 1-yl}-ethyl)-piperidin-3-yl]-acetamide 355 (rac,trans)-1-[(E)-3-(3,4-Dichloro- (rac,trans)-2-hydroxy- 454.2 phenyl)-acryloyl]-4-[2-(2-hydroxy- cyclohexylamine cyclohexylamino)-ethyl]-[1,4]diazepan- 5-one 356 4-(2-Cyclohexylamino-ethyl)-1-[(E)-3- cyclohexylamine 454.2 (3,4-dichloro-phenyl)-acryloyl]- [1,4]diazepan-5-one 357 (rac,cis)-1-[(E)-3-(3,4-Dichloro- (rac,cis)-2-hydroxy- 454.2 phenyl)-acryloyl]-4-[2-(2-hydroxy- cyclohexylamine cyclohexylamino)-ethyl]-[1,4]diazepan- 5-one

Examples 358-381 General Procedure for Examples 358-381

A solution of (rac)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-oxiranylmethyl-[1,4]diazepan-5-one (example 166A) (0.1 mmol) in DMA (0.5 ml) was added to the appropriate amine (0.15 mmol), which are either commercially available or are described in the intermediate section, and a generous spatula of cesium carbonate added. The reaction was then shaken overnight at 80° C., filtered, and directly purifed purified by preparative HPLC.

Example MS: No. Compound Name Amine (MH⁺) 358 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methyl- 498.3 acryloyl]-4-[3-hydroxy-4-(4-hydroxy-3- piperidin-4-ol methyl-piperidin-1-yl)-butyl]- (intermediate 94) [1,4]diazepan-5-one 359 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-4-methyl- 498.3 acryloyl]-4-[3-hydroxy-4-(3-hydroxy-4- piperidin-3-ol methyl-piperidin-1-yl)-butyl]- (intermediate 91) [1,4]diazepan-5-one 360 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- 4-methoxymethyl- 512.3 acryloyl]-4-[3-hydroxy-4-(4- piperidine methoxymethyl-piperidin-1-yl)-butyl]- [1,4]diazepan-5-one 361 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methoxymethyl- 512.3 acryloyl]-4-[3-hydroxy-4-(3- piperidine methoxymethyl-piperidin-1-yl)-butyl]- [1,4]diazepan-5-one 362 1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-2-methyl- 498.3 acryloyl]-4-[3-hydroxy-4-(trans-3- piperidin-3-ol hydroxy-2-methyl-piperidin-1-yl)- (intermediate 87) butyl]-[1,4]diazepan-5-one 363 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-(2-methyl- 512.3 acryloyl]-4-[3-hydroxy-4-(2- piperidin-2-yl)-methanol hydroxymethyl-2-methyl-piperidin-1- (intermediate 34) yl)-butyl]-[1,4]diazepan-5-one 364 (rac)-[1-(4-{4-[(E)-3-(3,4-Dichloro- Piperidin-4-yl-carbamic 541.3 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- acid methylester 1-yl}-2-hydroxy-butyl)-piperidin-4-yl]- (intermediate 38) carbamic acid methyl ester 365 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-4-Fluoro- 502.3 acryloyl]-4-[4-(trans-4-fluoro-3- piperidin-3-ol hydroxy-piperidin-1-yl)-3-hydroxy- (intermediate 89) butyl]-[1,4]diazepan-5-one 366 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-hydroxymethyl- 514.5 acryloyl]-4-[3-hydroxy-4-(4-hydroxy-3- piperidin-4-ol hydroxymethyl-piperidin-1-yl)-butyl]- (intermediate 35) [1,4]diazepan-5-one 367 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methoxymethyl- 528.5 acryloyl]-4-[3-hydroxy-4-(4-hydroxy-3- piperidin-4-ol methoxymethyl-piperidin-1-yl)-butyl]- (intermediate 36) [1,4]diazepan-5-one 368 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-4-methoxy-3- 542.5 acryloyl]-4-[3-hydroxy-4-(4-methoxy-3- methoxymethyl methoxymethyl-piperidin-1-yl)-butyl]- piperidine (intermediate [1,4]diazepan-5-one 37) 369 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-2- 514.5 acryloyl]-4-[3-hydroxy-4-(trans-4- hydroxymethyl- hydroxy-2-hydroxymethyl-piperidin-1- piperidin-4-ol yl)-butyl]-[1,4]diazepan-5-one (intermediate 46) 370 (rac)-N-[1-(4-{4-[(E)-3-(3,4-Dichloro- N-Piperidin-4-yl- 525.5 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- acetamide 1-yl}-2-hydroxy-butyl)-piperidin-4-yl]- acetamide 371 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-4-methyl- 498.5 acryloyl]-4-[3-hydroxy-4-(trans-3- piperidin-3-ol hydroxy-4-methyl-piperidin-1-yl)- (intermediate 100) butyl]-[1,4]diazepan-5-one 372 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-3-methyl- 498.5 acryloyl]-4-[3-hydroxy-4-(trans-4- piperidin-4-ol hydroxy-3-methyl-piperidin-1-yl)- (intermediate 95) butyl]-[1,4]diazepan-5-one 373 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-2-methoxymethyl- 512.3 acryloyl]-4-[3-hydroxy-4-(2- piperidine methoxymethyl-piperidin-1-yl)-butyl]- [1,4]diazepan-5-one 374 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-2-hydroxymethyl- 498.3 acryloyl]-4-[3-hydroxy-4-(2- piperidine hydroxymethyl-piperidin-1-yl)-butyl]- [1,4]diazepan-5-one 375 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-2-methylpiperidine 482.3 acryloyl]-4-[3-hydroxy-4-(2-methyl- piperidin-1-yl)-butyl]-[1,4]diazepan-5- one 376 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methylpiperidine 482.3 acryloyl]-4-[3-hydroxy-4-(3-methyl- piperidin-1-yl)-butyl]-[1,4]diazepan-5-one 377 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- 4-methylpiperidine 482.3 acryloyl]-4-[3-hydroxy-4-(4-methyl- piperidin-1-yl)-butyl]-[1,4]diazepan-5- one 378 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-hydroxymethyl- 498.3 acryloyl]-4-[3-hydroxy-4-(3- piperidine hydroxymethyl-piperidin-1-yl)-butyl]- [1,4]diazepan-5-one 379 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- 4-hydroxymethyl- 498.3 acryloyl]-4-[3-hydroxy-4-(4- piperidine hydroxymethyl-piperidin-1-yl)-butyl]- [1,4]diazepan-5-one 380 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methoxymethyl- 526.4 acryloyl]-4-[3-hydroxy-4-(3- 3-methyl-piperidine methoxymethyl-3-methyl-piperidin-1- (intermediate 31) yl)-butyl]-[1,4]diazepan-5-one 381 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-2-hydroxymethyl- 498.3 acryloyl]-4-[3-hydroxy-4-(2- 2-methyl-pyrrolidine hydroxymethyl-2-methyl-pyrrolidin-1- yl)-butyl]-[1,4]diazepan-5-one

Examples 382-409 General Procedure for Examples 382-409

A solution of 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one (intermediate 99) (0.1 mmol) in DMA (0.5 ml) was added to the appropriate amine (0.15 mmol), which are either commercially available or are described in the intermediate section, and a generous spatula of cesium carbonate and sodium iodide added. The reaction was then shaken at room termperature for 1 h, then raised to 80° C. for a further 1 h, filtered, and directly purifed purified by preparative HPLC.

Example MS: No. Compound Name Amine (MH⁺) 382 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- Piperidine 436.3 acryloyl]-4-(4-piperidin-1-yl-butyl)- [1,4]diazepan-5-one 383 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac)-piperidin-3-ol 452.3 phenyl)-acryloyl]-4-[4-(3-hydroxy- piperidin-1-yl)-butyl]-[1,4]diazepan-5- one 384 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- Piperidin-4-ol 452.3 acryloyl]-4-[4-(4-hydroxy-piperidin-1- yl)-butyl]-[1,4]diazepan-5-one 385 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac)-3-hydroxymethyl- 466.3 phenyl)-acryloyl]-4-[4-(3- piperidine hydroxymethyl-piperidin-1-yl)-butyl]- [1,4]diazepan-5-one 386 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- 4-hydroxymethyl- 466.3 acryloyl]-4-[4-(4-hydroxymethyl- piperidine piperidin-1-yl)-butyl]-[1,4]diazepan-5- one 387 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac)-2-hydroxymethyl- 466.3 phenyl)-acryloyl]-4-[4-(2- piperidine hydroxymethyl-piperidin-1-yl)-butyl]- [1,4]diazepan-5-one 388 (rac,trans)-1-[(E)-3-(3-Chloro-4- (rac,trans)-2-methyl- 466.3 fluoro-phenyl)-acryloyl]-4-[4-(3- piperidin-3-ol hydroxy-2-methyl-piperidin-1-yl)- (intermediate 87) butyl]-[1,4]diazepan-5-one 389 (rac,trans)-1-[(E)-3-(3-Chloro-4- (rac,trans)-4-Fluoro- 470.3 fluoro-phenyl)-acryloyl]-4-[4-(4-fluoro- piperidin-3-ol 3-hydroxy-piperidin-1-yl)-butyl]- (intermediate 89) [1,4]diazepan-5-one 390 (rac,cis)-1-[(E)-3-(3-Chloro-4-fluoro- (rac,cis)-3-fluoro- 470.3 phenyl)-acryloyl]-4-[4-(3-fluoro-4- piperidin-4-ol hydroxy-piperidin-1-yl)-butyl]- (intermediate 93) [1,4]diazepan-5-one 391 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac)-3-methyl- 466.3 phenyl)-acryloyl]-4-[4-(3-hydroxy-3- piperidin-3-ol methyl-piperidin-1-yl)-butyl]- (intermediate 101) [1,4]diazepan-5-one 392 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac)-3-methoxymethyl- 480.3 phenyl)-acryloyl]-4-[4-(3- piperidine methoxymethyl-piperidin-1-yl)-butyl]- [1,4]diazepan-5-one 393 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac)-3-hydroxy- 438.3 phenyl)-acryloyl]-4-[4-(3-hydroxy- pyrrolidine pyrrolidin-1-yl)-butyl]-[1,4]diazepan-5- one 394 (rac,trans)-1-[(E)-3-(3-Chloro-4- (rac,trans)-3-fluoro- 470.3 fluoro-phenyl)-acryloyl]-4-[4-(3-fluoro- piperidin-4-ol 4-hydroxy-piperidin-1-yl)-butyl]- (intermediate 90) [1,4]diazepan-5-one 395 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac)-3- 466.3 phenyl)-acryloyl]-4-[4-(3-methoxy- methoxypiperidine piperidin-1-yl)-butyl]-[1,4]diazepan-5- one 396 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- 1-Isopropyl-piperazine 479.4 acryloyl]-4-[4-(4-isopropyl-piperazin-1- yl)-butyl]-[1,4]diazepan-5-one 397 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- 1-Cyclopropyl- 477.3 acryloyl]-4-[4-(4-cyclopropyl-piperazin- piperazine 1-yl)-butyl]-[1,4]diazepan-5-one 389 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- 1-Cyclopentyl-piperazine 505.4 acryloyl]-4-[4-(4-cyclopentyl-piperazin- 1-yl)-butyl]-[1,4]diazepan-5-one 399 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- 1-(2-Methoxy-ethyl)- 495.4 acryloyl]-4-{4-[4-(2-methoxy-ethyl)- piperazine piperazin-1-yl]-butyl}-[1,4]diazepan-5- one 400 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac)-3-methyl- 466.3 phenyl)-acryloyl]-4-[4-(4-hydroxy-3- piperidin-4-ol methyl-piperidin-1-yl)-butyl]- (intermediate 94) [1,4]diazepan-5-one 401 [1-(4-{4-[(E)-3-(3-Chloro-4-fluoro- Piperidin-4-yl-carbamic 509.3 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- acid methylester 1-yl}-butyl)-piperidin-4-yl]-carbamic (intermediate 38) acid methyl ester 402 [1-(4-{4-[(E)-3-(3-Chloro-4-fluoro- Methyl-piperidin-4-yl- 523.3 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- carbamic acid methyl 1-yl}-butyl)-piperidin-4-yl]-methyl ester (intermediate 39) carbamic acid methyl ester 403 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac)-1-Isopropyl-2- 493.4 phenyl)-acryloyl]-4-[4-(4-isopropyl-3- methyl-piperazine methyl-piperazin-1-yl)-butyl]- [1,4]diazepan-5-one 404 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- 4-methoxymethyl- 480.4 acryloyl]-4-[4-(4-methoxymethyl- piperidine piperidin-1-yl)-butyl]-[1,4]diazepan-5- one 405 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac)-(3-methyl- 480.4 phenyl)-acryloyl]-4-[4-(3-hydroxy-3- piperidin-3-yl)-methanol methyl-piperidin-1-yl)-butyl]- (intermediate 30) [1,4]diazepan-5-one 406 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac)-3-methoxymethyl- 494.4 phenyl)-acryloyl]-4-[4-(3- 3-methyl-piperidine methoxymethyl-3-methyl-piperidin-1- (intermediate 31) yl)-butyl]-[1,4]diazepan-5-one 407 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac)-(2-methyl- 480.4 phenyl)-acryloyl]-4-[4-(2- piperidin-2-yl)-methanol hydroxymethyl-2-methyl-piperidin-1- (intermediate 34) yl)-butyl]-[1,4]diazepan-5-one 408 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac,cis)-2- 482.3 phenyl)-acryloyl]-4-[4-(cis-4-hydroxy-2- hydroxymethyl- hydroxymethyl-piperidin-1-yl)-butyl]- piperidin-4-ol) [1,4]diazepan-5-one (intermediate 45) 409 (rac)-1-[(E)-3-(3-Chloro-4-fluoro- (rac)-4-methyl- 466.3 phenyl)-acryloyl]-4-[4-(4-hyroxy-3- piperidin-3-ol methyl-piperidin-1-yl)-butyl]- (intermediate 91) [1,4]diazepan-5-one

Examples 410-421 General Procedure for Examples 410-421

A solution of 1-[(E)-3-(4-Chloro-3-fluoro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one (intermediate 57) (0.1 mmol) in DMA (0.5 ml) was added to the appropriate amine (0.15 mmol), which are either commercially available or are described in the intermediate section, and a generous spatula of cesium carbonate and sodium iodide added. The reaction was then shaken at room termperature for 1 h, then raised to 80° C. for a further 1 h, filtered, and directly purifed purified by preparative HPLC.

Example MS: No. Compound Name Amine (MH⁺) 410 (rac)-1-[(E)-3-(4-Chloro-3-fluoro- (rac,cis)-(3-methoxy- 496.4 phenyl)-acryloyl]-4-[4-(cis-3-methoxy- piperidin-4-yl)-methanol 4-hydroxymethyl-piperidin-1-yl)-butyl]- (intermediate 50) [1,4]diazepan-5-one 411 (rac)-1-[(E)-3-(4-Chloro-3-fluoro- (rac,cis)-4- 496.4 phenyl)-acryloyl]-4-[4-(cis-3-hydroxy-4- hydroxymethyl-4- hydroxymethyl-4-methyl-piperidin-1- methyl-piperidin-3-ol yl)-butyl]-[1,4]diazepan-5-one (intermediate 52) 412 (rac)-1-[(E)-3-(4-Chloro-3-fluoro- (rac,trans)-4- 496.4 phenyl)-acryloyl]-4-[4-(trans-3- hydroxymethyl-4- hydroxy-4-hydroxymethyl-4-methyl- methyl-piperidin-3-ol piperidin-1-yl)-butyl]-[1,4]diazepan-5- (intermediate 53) one 413 (rac)-1-[(E)-3-(4-Chloro-3-fluoro- (rac)-6methyl-piperidin- 466.4 phenyl)-acryloyl]-4-[4-(5-hydroxy-2- 3-ol (intermediate 66) methyl-piperidin-1-yl)-butyl]- [1,4]diazepan-5-one 414 (rac)-1-[(E)-3-(4-Chloro-3-fluoro- (rac)-6-ydroxymethyl- 482.4 phenyl)-acryloyl]-4-[4-(5-hydroxy-2- piperidin-3-ol hydroxymethyl-piperidin-1-yl)-butyl]- (intermediate 65) [1,4]diazepan-5-one 415 1-[(E)-3-(4-Chloro-3-fluoro-phenyl)- (+)-6-Aza- 478.4 acryloyl]-4-[4-((+)-4-hydroxy-6-aza- spiro[2.5]octan-4-ol spiro[2.5]oct-6-yl)-butyl]-[1,4]diazepan- (intermediate 82) 5-one 416 1-[(E)-3-(4-Chloro-3-fluoro-phenyl)- (−)-6-Aza- 478.4 acryloyl]-4-[4-((−)-4-hydroxy-6-aza- spiro[2.5]octan-4-ol spiro[2.5]oct-6-yl)-butyl]-[1,4]diazepan- (intermediate 83) 5-one 417 (rac)-1-[(E)-3-(4-Chloro-3-fluoro- (rac)-(5-methoxy- 496.3 phenyl)-acryloyl]-4-[4-(2- piperidin-2-yl)-methanol hydroxymethyl-5-methoxy-piperidin-1- (intermediate 67) yl)-butyl]-[1,4]diazepan-5-one 418 (rac)-1-[(E)-3-(4-Chloro-3-fluoro- (rac)-6-methoxymethyl- 496.4 phenyl)-acryloyl]-4-[4-(5-hydroxy-2- pipeirdin-3-ol methoxymethyl-piperidin-1-yl)-butyl]- (intermediate 74) [1,4]diazepan-5-one 419 (rac)-1-[(E)-3-(4-Chloro-3-fluoro- (rac,cis)-2- 482.3 phenyl)-acryloyl]-4-[4-(cis-3-hydroxy-2- hydroxymethyl- hydroxymethyl-piperidin-1-yl)-butyl]- piperidin-3-ol [1,4]diazepan-5-one (intermediate 62) 420 (rac)-1-[(E)-3-(4-Chloro-3-fluoro- (rac)-4,4-dimethyl- 480.3 phenyl)-acryloyl]-4-[4-(3-hydroxy-4,4- piperidin-3-ol dimethyl-piperidin-1-yl)-butyl]-[1,4]- (intermediate 84) diazepan-5-one 421 (rac,cis)-1-[(E)-3-(4-Chloro-3-fluoro- (rac,cis)-5-methyl- 466.3 phenyl)-acryloyl]-4-[4-(3-hydroxy-5- piperidin-3-ol methyl-piperidin-1-yl)-butyl]- (intermediate 75) [1,4]diazepan-5-one

Examples 422-490 General Procedure for Examples 422-490

A solution of 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one (Example 9B) (0.1 mmol) in DMA (0.5 ml) was added to the appropriate amine (0.15 mmol), which are either commercially available or are described in the intermediate section, and a generous spatula of cesium carbonate and sodium iodide added. The reaction was then shaken at room termperature for 1 h, then raised to 80° C. for a further 1 h, filtered, and directly purifed purified by preparative HPLC.

Example MS: No. Compound Name Amine (MH⁺) 422 1-[(E)-3-(3,4-Dichloro-phenyl)- 4-hydroxymethyl- 482.3 acryloyl]-4-[4-(4-hydroxymethyl- piperidine piperidin-1-yl)-butyl]-[1,4]diazepan-5- one 423 1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methoxymethyl- 496.3 acryloyl]-4-[4-(3-methoxymethyl- piperidine piperidin-1-yl)-butyl]-[1,4]diazepan-5- one 424 1-[(E)-3-(3,4-Dichloro-phenyl)- piperidin-4-ol 468.3 acryloyl]-4-[4-(4-hydroxy-piperidin-1- yl)-butyl]-[1,4]diazepan-5-one 425 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-hydroxymethyl- 482.3 acryloyl]-4-[4-(3-hydroxymethyl- piperidine piperidin-1-yl)-butyl]-[1,4]diazepan-5- one 426 1-[(E)-3-(3,4-Dichloro-phenyl)- 4-hydroxymethyl- 482.3 acryloyl]-4-[4-(4-hydroxymethyl- piperidine piperidin-1-yl)-butyl]-[1,4]diazepan-5- one 427 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-2-hydroxymethyl- 482.3 acryloy]-4-[4-(2-hydroxymethyl- piperidine piperidin-1-yl)-butyl]-[1,4]diazepan-5- one 428 (rac,trans)-1-[(E)3-(3,4-Dichloro- (rac,trans)-2-methyl- 482.3 phenyl)-acryloyl]-4-[4-(3-hydroxy-2- piperidin-3-ol methyl-piperidin-1-yl)-butyl]- (intermediate 87) [1,4]diazepan-5-one 429 (rac,trans)-1-[(E)-3-(3,4-Dichloro- (rac,trans)-4-Fluoro- 486.2 phenyl)-acryloyl]-4-[4-(4-fluoro-3- piperidin-3-ol hydroxy-piperidin-1-yl)-butyl]- (intermediate 89) [1,4]diazepan-5-one 430 (rac,cis)-1-[(E)-3-(3,4-Dichloro- (rac,cis)-3-fluoro- 486.2 phenyl)-acryloyl]-4-[4-(3-fluoro-4- piperidin-4-ol hydroxy-piperidin-1-yl)-butyl]- (intermediate 93) [1,4]diazepan-5-one 431 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methyl- 482.3 acryloyl]-4-[4-(3-hydroxy-3-methyl- piperidin-3-ol piperidin-1-yl)-butyl]-[1,4]diazepan-5- (intermediate 101) one 432 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-Methoxymethyl- 496.3 acryloyl]-4-[4-(3-methoxymethyl- piperidine piperidin-1-yl)-butyl]-[1,4]diazepan-5- one 433 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-Pyrrolidin-3-ol 454.2 acryloyl]-4-[4-(3-hydroxy-pyrrolidin-1- yl)-butyl]-[1,4]diazepan-5-one 434 (rac,trans)-1-[(E)-3-(3,4-Dichloro- (rac,trans)-3-fluoro- 486.2 phenyl)-acryloyl]-4-[4-(3-fluoro-4- piperidin-4-ol hydroxy-piperidin-1-yl)-butyl]- (intermediate 90) [1,4]diazepan-5-one 435 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3- 482.3 acryloyl]-4-[4-(3-methoxy-piperidin-1- methoxypiperidine yl)-butyl]-[1,4]diazepan-5-one 436 1-[(E)-3-(3,4-Dichloro-phenyl)- 1-Isopropyl-piperazine 495.3 acryloyl]-4-[4-(4-isopropyl-piperazin-1- yl)-butyl]-[1,4]diazepan-5-one 437 1-[(E)-3-(3,4-Dichloro-phenyl)- 1-Cyclopropyl- 493.3 acryloyl]-4-[4-(4-cyclopropyl-piperazin- piperazine 1-yl)-butyl]-[1,4]diazepan-5-one 438 1-[(E)-3-(3,4-Dichloro-phenyl)- 1-Cyclopentyl-piperazine 521.3 acryloyl]-4-[4-(4-cyclopentyl-piperazin- 1-yl)-butyl]-[1,4]diazepan-5-one 439 1-[(E)-3-(3,4-Dichloro-phenyl)- 1-(2-Methoxy-ethyl)- 511.3 acryloyl]-4-{4-[4-(2-methoxy-ethyl)- piperazine piperazin-1-yl]-butyl}-[1,4]diazepan-5- one 440 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methyl- 482.3 acryloyl]-4-[4-(4-hydroxy-3-methyl- piperidin-4-ol piperidin-1-yl)-butyl]-[1,4]diazepan-5- (intermediate 94) one 441 [1-(4-{4-[(E)-3-(3,4-Dichloro-phenyl)- Piperidin-4-yl-carbamic 525.3 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- acid methylester butyl)-piperidin-4-yl]-carbamic acid (intermediate 38) methyl ester 442 [1-(4-{4-[(E)-3-(3,4-Dichloro-phenyl)- Methyl-piperidin-4-yl- 539.3 acryloyl]-7-oxo-[1,4]diazepan-1-yl}- carbamic acid methyl butyl)-piperidin-4-yl]-methyl-carbamic ester (intermediate 39) acid methyl ester 443 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-1-Isopropyl-2- 509.3 acryloyl]-4-[4-(4-isopropyl-3-methyl- methyl-piperazine piperazin-1-yl)-butyl]-[1,4]diazepan-5- one 444 1-[(E)-3-(3,4-Dichloro-phenyl)- 4-methoxymethyl- 496.3 acryloyl]-4-[4-(4-methoxymethyl-3- piperidine piperidin-1-yl)-butyl]-[1,4]diazepan-5- one 445 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-(3-methyl- 496.4 acryloyl]-4-[4-(3-hydroxymethyl-3- piperidin-3-yl)-methanol methyl-piperidin-1-yl)-butyl]- (intermediate 30) [1,4]diazepan-5-one 446 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methoxymethyl- 510.4 acryloyl]-4-[4-(3-methoxymethyl-3- 3-methyl-piperidine methyl-piperidin-1-yl)-butyl]- (intermediate 31) [1,4]diazepan-5-one 447 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-(2-methyl- 496.3 acryloyl]-4-[4-(2-hydroxymethyl-2- piperidin-2-yl)-methanol methyl-piperidin-1-yl)-butyl]- (intermediate 34) [1,4]diazepan-5-one 448 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-4-methyl- 482.3 acryloyl]-4-[4-(3-hydroxy-4-methyl- piperidin-3-ol piperidin-1-yl)-butyl]-[1,4]diazepan-5- (intermediate 91) one 449 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-2-methoxymethyl- 496.4 acryloyl]-4-[4-(2-methoxymethyl- piperidine piperidin-1-yl)-butyl]-[1,4]diazepan-5- one 450 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-hydroxymethyl- 498.5 acryloyl]-4-[4-(4-hydroxy-3- piperidin-4-ol hydroxymethyl-piperidin-1-yl)-butyl]- (intermediate 35) [1,4]diazepan-5-one 451 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3-methoxymethyl- 512.5 acryloyl]-4-[4-(4-hydroxy-3- piperidin-4-ol methoxymethyl-piperidin-1-yl)-butyl]- (intermediate 36) [1,4]diazepan-5-one 452 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-4-methoxy-3- 526.6 acryloyl]-4-[4-(4-methoxy-3- methoxymethyl- methoxymethyl-piperidin-1-yl)-butyl]- piperidine (intermediate [1,4]diazepan-5-one 37) 453 N-[1-(4-{4-[(E)-3-(3,4-Dichloro- N-Piperidin-4-yl- 509.5 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- acetamide 1-yl}-butyl)-piperidin-4-yl]-acetamide 454 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-4-methyl- 482.5 acryloyl]-4-[4-(trans-3-hydroxy-4- piperidin-3-ol methyl-piperidin-1-yl)-butyl]- (intermediate 100) [1,4]diazepan-5-one 455 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-3-methyl- 482.5 acryloyl]-4-[4-(trans-4-hydroxy-3- piperidin-4-ol methyl-piperidin-1-yl)-butyl]- (intermediate 95) [1,4]diazepan-5-one 456 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-6-Aza- 494.3 acryloyl]-4-[4-(4-hydroxy-6-aza- spiro[2.5]octan-4-ol spiro[2.5]oct-6-yl)-butyl]-[1,4]diazepan- (intermediate 81) 5-one 457 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-5-Aza- 494.3 acryloyl]-4-[4-(8-hydroxy-5-aza- spiro[2.5]octan-8-ol spiro[2.5]oct-5-yl)-butyl]-[1,4]diazepan- (intermediate 98) 5-one 458 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,cis)-3-methyl- 482.3 acryloyl]-4-[4-(cis-4-hydroxy-3-methyl- piperidin-4-ol piperidin-1-yl)-butyl]-[1,4]diazepan-5- (intermediate 96) one 459 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (4-methyl-piperidin-4- 496.3 acryloyl]-4-[4-(4-hydroxymethyl-4- yl)-methanol methyl-piperidin-1-yl)-butyl]- (intermediate 32) [1,4]diazepan-5-one 460 1-[(E)-3-(3,4-Dichloro-phenyl)- 2-Methylamino-ethanol 442.3 acryloyl]-4-{4-[(2-hydroxy-ethyl)- methyl-amino]-butyl}-[1,4]diazepan-5- one 461 1-[(E)-3-(3,4-Dichloro-phenyl)- 2-Ethylamino-ethanol 456.3 acryloyl]-4-{4-[(2-hydroxy-ethyl)-ethyl- amino]-butyl}-[1,4]diazepan-5-one 462 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-(2-methyl- 482.3 acryloyl]-4-[4-(2-hydroxymethyl-2- pyrrolidin-2-yl)- methyl-pyrrolidin-1-yl)-butyl]- methanol (intermediate [1,4]diazepan-5-one 34) 463 (rac)-N-[1-(4-{4-[(E)-3-(3,4-Dichloro- (rac)-Piperidin-3-yl- 525.4 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- carbamic acid methyl 1-yl}-butyl)-piperidin-3-yl]-acetamide ester (intermediate 40) 464 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-3,3-dimethyl- 496.4 acryloyl]-4-[4-(4-hydroxy-3,3-dimethyl- piperidin-4-ol piperidin-1-yl)-butyl]-[1,4]diazepan-5- (intermediate 97) one 465 1-[(E)-3-(3,4-Dichloro-phenyl)- 1-Isobutyl-piperazine 509.4 acryloyl]-4-[4-(4-isobutyl-piperazin-1- yl)-butyl]-[1,4]diazepan-5-one 466 (rac)-N-[1-(4-{4-[(E)-3-(3,4-Dichloro- (rac)-N-Piperidin-3-yl- 509.4 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- acetamide 1-yl}-butyl)-piperidin-3-yl]-acetamide 467 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- 1-Oxa-8-aza- 508.4 acryloyl]-4-[4-(1-oxa-8-aza- spiro[4.5]decane Spiro[4.5]dec-8-yl)-butyl]- (intermediate 27) [1,4]diazepan-5-one 468 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,cis)-4- 498.4 acryloyl]-4-[4-(cis-3-hydroxy-4- hydroxymethyl- hydroxymethyl-piperidin-1-yl)-butyl]- piperidin-3-ol [1,4]diazepan-5-one (intermediate 47) 469 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,cis)-4- 512.4 acryloyl]-4-[4-(cis-3-hydroxy-4- methoxymethyl- methoxymethyl-piperidin-1-yl)-butyl]- piperidin-3-ol [1,4]diazepan-5-one (intermediate 49) 470 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,cis)-3-methoxy-4- 526.4 acryloyl]-4-[4-(cis-3-methoxy-4- methoxymethyl- methoxymethyl-piperidin-1-yl)-butyl]- piperidine (intermediate [1,4]diazepan-5-one 51) 471 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-4- 498.4 acryloyl]-4-[4-(trans-3-hydroxy-4- hydroxymethyl- hydroxymethyl-piperidin-1-yl)-butyl]- piperidin-3-ol [1,4]diazepan-5-one (intermediate 48) 472 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,cis)-(3-methoxy- 512.4 acryloyl]-4-[4-(cis-3-methoxy-4- piperidin-4-yl)-methanol hydroxymethyl-piperidin-1-yl)-butyl]- (intermediate 50) [1,4]diazepan-5-one 473 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,cis)-4- 512.4 acryloyl]-4-[4-(cis-3-hydroxy-4- hydroxymethyl-4- hydroxymethyl-4-methyl-piperidin-1- methyl-piperidin-3-ol yl)-butyl]-[1,4]diazepan-5-one (intermediate 52) 474 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-4- 512.4 acryloyl]-4-[4-(trans-3-hydroxy-4- hydroxymethyl-4- hydroxymethyl-4-methyl-piperidin-1- methyl-piperidin-3-ol yl)-butyl]-[1,4]diazepan-5-one (intermediate 53) 475 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-6-methyl- 482.4 acryloyl]-4-[4-(5-hydroxy-2-methyl- piperidin-3-ol piperidin-1-yl)-butyl]-[1,4]diazepan-5- (intermediate 66) one 476 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-6-hydroxymethyl- 498.4 acryloyl]-4-[4-(5-hydroxy-2- piperidin-3-ol hydroxymethyl-piperidin-1-yl)-butyl]- (intermediate 65) [1,4]diazepan-5-one 477 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-(5-methoxy- 512.3 acryloyl]-4-[4-(2-hydroxymethyl-5- piperidin-2-yl)-methanol methoxy-piperidin-1-yl)-butyl]- (intermediate 67) [1,4]diazepan-5-one 478 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-4-methoxy-6- 542.3 acryloyl]-4-[4-(5-hydroxy-4-methoxy-2- methoxymethyl- methoxymethyl-piperidin-1-yl)-butyl]- piperidin-3-ol [1,4]diazepan-5-one (intermediate 68) 479 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-6-methoxymethyl- 512.3 acryloyl]-4-[4-(5-hydroxy-2- piperidin-3-ol methoxymethyl-piperidin-1-yl)-butyl]- (intermediate 63) [1,4]diazepan-5-one 480 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,cis)-2- 498.3 acryloyl]-4-[4-(cis-3-hydroxy-2- hydroxymethyl- hydroxymethyl-piperidin-1-yl)-butyl]- piperidin-3-ol [1,4]diazepan-5-one (intermediate 62) 481 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-4,4-dimethyl- 496.3 acryloyl]-4-[4-(4-hydroxy-4,4-dimethyl- piperidin-3-ol piperidin-1-yl)-butyl]-[1,4]diazepan-5- (intermediate 84) one 482 (rac,cis)-1-[(E)-3-(3,4-Dichloro- (rac,cis)-5-methyl- 482.3 phenyl)-acryloyl]-4-[4-(3-hydroxy-5- piperidin-3-ol methyl-piperidin-1-yl)-butyl]- (intermediate 75) [1,4]diazepan-5-one 483 (rac)-N-[(2RS,4SR,5RS)-1-(4-{4-[(E)-3- N-((2RS,4SR,5RS)-5- 583.3 (3,4-Dichloro-phenyl)-acryloyl]-7-oxo- Methoxy-2- [1,4]diazepan-1-yl}-butyl)-5-methoxy-2- methoxymethyl- methoxymethyl-piperidin-4-yl]- piperidin-4-yl)- acetamide acetamide (intermediate 69) 484 (rac,trans)-1-[(E)-3-(3,4-Dichloro- (rac,trans)-6- 512.3 phenyl)-acryloyl]-4-[4-(5-hydroxy-2- methoxymethyl- methoxymethyl-piperidin-1-yl)-butyl]- piperidin-3-ol [1,4]diazepan-5-one (intermediate 74) 485 (rac)-2-[1-(4-{4-[(E)-3-(3,4-Dichloro- (rac)-2-(6- 555.3 phenyl)-acryloyl]-7-oxo-[1,4]diazepan- Hydroxymethyl- 1-yl}-butyl)-6-hydroxymethyl-piperidin- piperidin-3-yloxy)- 3-yloxy]-acetamide acetamide (intermediate 72) 486 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-2-Methoxymethyl- 512.3 acryloyl]-4-[4-(3-hydroxy-2- piperidin-3-ol methoxymethyl-piperidin-1-yl)-butyl]- (intermediate 73) [1,4]diazepan-5-one 487 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac,trans)-6-Methyl- 482.3 acryloyl]-4-[4-(5-hydroxy-2-methyl- piperidin-3-ol piperidin-1-yl)-butyl]-[1,4]diazepan-5- (intermediate 70) one 488 (rac,cis)-1-[(E)-3-(3,4-Dichloro- (rac,cis)-2- 526.3 phenyl)-acryloyl]-4-[4-(3-hydroxy-2- Methoxymethyl-6- methoxymethyl-6-methyl-piperidin-1- methyl-piperidin-3-ol yl)-butyl]-[1,4]diazepan-5-one (intermediate 64) 489 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-2,6-Bis- 556.3 acryloyl]-4-[4-(3-hydroxy-2,6-bis- methoxymethyl- methoxymethyl-piperidin-1-yl)-butyl]- piperidin-3-ol [1,4]diazepan-5-one (intermediate 71) 490 (rac)-1-[(E)-3-(3,4-Dichloro-phenyl)- (rac)-5-Methoxymethyl- 498.3 acryloyl]-4-[4-(3-hydroxy-5- piperidin-3-ol methoxymethyl-piperidin-1-yl)-butyl]- (intermediate 76) [1,4]diazepan-5-one

Examples 491-494 General Procedure for Examples 491-494

A solution of 3-{4-[(E)-3-(4-Chloro-3-fluoro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propionaldehyde (intermediate 60) (0.1 mmol) in DCE (0.5 ml) was added to the appropriate amine (0.1 mmol), which are either commercially available or are described in the intermediate section, followed by a freshly prepared solution of pyridine-borane complex (25 ul, 8M in pyridine, 0.2 mmol) and acetic acid (25 ul) in EtOH (0.5 ml). The reaction was then shaken overnight, concentrated and the residue purified by preparative HPLC.

Ex- am- ple MS: No. Compound Name Amine (MH⁺) 491 1-[(E)-3-(4-Chloro-3-fluoro-phenyl)- (+,cis)-4-Methyl- 452.3 acryloyl]-4-[3-((+,cis)-3-hydroxy-4- piperidin-3-ol methyl-piperidin-1-yl)-propyl]- (intermediate 85) [1,4]diazepan-5-one 492 1-[(E)-3-(4-Chloro-3-fluoro-phenyl)- (−,cis)-4-Methyl- 452.3 acryloyl]-4-[3-((−,cis)-3-hydroxy-4- piperidin-3-ol methyl-piperidin-1-yl)-propyl]- (intermediate 86) [1,4]diazepan-5-one 493 1-[(E)-3-(4-Chloro-3-fluoro-phenyl)- (+)-6-Aza- 464.3 acryloyl]-4-[3-((+)-4-hydroxy-6-aza- spiro[2.5]octan- spiro[2.5]oct-6-yl)-propyl]- 4-ol [1,4]diazepan-5-one (intermediate 82) 494 1-[(E)-3-(4-Chloro-3-fluoro-phenyl)- (−)-6-Aza- 464.3 acryloyl]-4-[3-((−)-4-hydroxy-6-aza- spiro[2.5]octan- spiro[2.5]oct-6-yl)-propyl]- 4-ol [1,4]diazepan-5-one (intermediate 83)

Examples 495-498 General Procedure for Examples 495-498

To a suspension of 4-[3-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one dihydrochloride (intermediate 92, 0.1 mmol), O-(7-azabenotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol), the appropriate carboxylic acid in DMF (1 ml) was added Et₃N (21 ul, 0.15 mmol) and the mixture shaken for 1 h. The reaction was then directly purified by preparative HPLC.

Example MS: No. Compound Name Acid (MH⁺) 495 1-[(E)-3-(3,4-Difluoro-phenyl)- (E)-3-(3,4-Difluoro- 448.4 acryloyl]-4-[3-((−)-4-hydroxy-6-aza- phenyl)-acrylic spiro[2.5]oct-6-yl)-propyl]- acid [1,4]diazepan-5-one 496 1-[(E)-3-(3-Chloro-phenyl)-acryloyl]-4- (E)-3-(3-Chloro- 446.4 [3-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6- phenyl)-acrylic acid yl)-propyl]-[1,4]diazepan-5-one 497 1-[(E)-3-(5,6-Dichloro-pyridin-3-yl)- (E)-3-(5,6-Dichloro- 481.3 acryloyl]-4-[3-((−)-4-hydroxy-6-aza- pyridin-3-yl)-acrylic acid spiro[2.5]oct-6-yl)-propyl]- (Example 12B) [1,4]diazepan-5-one 498 1-[(E)-3-(4-Chloro-phenyl)-acryloyl]-4- (E)-3-(4-Chloro- 446.4 [3-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6- phenyl)-acrylic acid yl)-propyl]-[1,4]diazepan-5-one

Examples 499-501 General Procedure for Examples 499-501

A solution of (rac)-4,4-dimethyl-piperidin-3-ol hydrochloride (intermediate 84) (0.15 mmol) in DMA (0.5 ml) was added to the appropriate epoxide (0.10 mmol) and a generous spatula of cesium carbonate added. The reaction was then shaken overnight at 80° C., filtered, and directly purifed purified by preparative HPLC.

MS: Example No. Compound Name Epoxide (MH⁺) 499 (rac)-1-[(E)-3-(3,4-Difluoro-phenyl)- (rac)-1-[(E)-3-(3,4- 466.3 acryloyl]-4-[2-hydroxy-3-(3-hydroxy- Difluoro-phenyl)- 4,4-dimethyl-piperidin-1-yl)-propyl]- acryloyl]-4- [1,4]diazepan-5-one oxiranylmethyl- [1,4]diazepan-5-one (Example 177A) 500 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- 1-[(E)-3-(3-Chloro-4- 496.3 acryloyl]-4-[(R)-3-hydroxy-4-(3- fluoro-phenyl)-acryloyl]- hydroxy-4,4-dimethyl-piperidin-1-yl)- 4-((R)-2-oxiranyl-ethyl)- butyl]-[1,4]diazepan-5-one [1,4]diazepan-5-one (intermediate 56) 501 1-[(E)-3-(3,4-Dichloro-phenyl)- 1-[(E)-3-(3,4-Dichloro- 512.3 acryloyl]-4-[(R)-3-hydroxy-4-(3- phenyl)-acryloyl]-4- hydroxy-4,4-dimethyl-piperidin-1-yl)- ((R)-2-oxiranyl-ethyl)- butyl]-[1,4]diazepan-5-one [1,4]diazepan-5-one (Example 172C)

Examples 502-505 General Procedure for Examples 502-505

A solution of (rac, cis)-5-methyl-piperidine-3-ol hydrochloride (intermediate 75) (0.15 mmol) in DMA (0.5 ml) was added to the appropriate epoxide (0.10 mmol) and a generous spatula of cesium carbonate added. The reaction was then shaken overnight at 80° C., filtered, and directly purifed purified by preparative HPLC.

MS: Example No. Compound Name Epoxide (MH⁺) 502 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)- 1-[(E)-3-(3-Chloro-4- 482.3 acryloyl]-4-[(R)-3-hydroxy-4-(cis-3- fluoro-phenyl)-acryloyl]- hydroxy-5-methyl-piperidin-1-yl)- 4-((R)-2-oxiranyl-ethyl)- butyl]-[1,4]diazepan-5-one [1,4]diazepan-5-one (intermediate 56) 503 1-[(E)-3-(3,4-Dichloro-phenyl)- 1-[(E)-3-(3,4-Dichloro- 498.3 acryloyl]-4-[(R)-3-hydroxy-4-(cis-3- phenyl)-acryloyl]-4- hydroxy-5-methyl-piperidin-1-yl)- ((R)-2-oxiranyl-ethyl)- butyl]-[1,4]diazepan-5-one [1,4]diazepan-5-one (Example 172C) 504 (rac)-1-[(E)-3-(3,4-Difluoro-phenyl)- (rac)-1-[(E)-3-(3,4- 452.3 acryloyl]-4-[2-hydroxy-3-(cis-3- Difluoro-phenyl)- hydroxy-5-methyl-piperidin-1-yl)- acryloyl]-4- propyl]-[1,4]diazepan-5-one oxiranylmethyl- [1,4]diazepan-5-one (Example 177A) 505 (rac)-1-[(E)-3-(3,4-Difluoro-phenyl)- (rac)-1-[(E)-3-(3,4- 466.3 acryloyl]-4-[3-hydroxy-4-(cis-3- Difluoro-phenyl)- hydroxy-5-methyl-piperidin-1-yl)- acryloyl]-4-(2-oxiranyl- butyl]-[1,4]diazepan-5-one ethyl)-[1,4]diazepan-5- one (intermediate 58)

Example A

Film coated tablets containing the following ingredients can be manufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mg  Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mg Magnesium stearate  1.5 mg  4.5 mg (Kernel Weight) 120.0 mg  350.0 mg  Film Coat: Hydroxypropyl methyl cellulose  3.5 mg  7.0 mg Polyethylene glycol 6000  0.8 mg  1.6 mg Talc  1.3 mg  2.6 mg Iron oxyde (yellow)  0.8 mg  1.6 mg Titan dioxide  0.8 mg  1.6 mg

The active ingredient is sieved and mixed with microcristalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidon in water. The granulate is mixed with sodium starch glycolate and magesiumstearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aqueous solution/suspension of the above mentioned film coat.

Example B

Capsules containing the following ingredients can be manufactured in a conventional manner:

Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mg  Maize starch 20.0 mg Talc  5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example C

Injection solutions can have the following composition:

Compound of formula (I) 3.0 mg Polyethylene Glycol 400 150.0 mg Acetic Acid q.s. ad pH 5.0 Water for injection solutions Ad 1.0 ml

The active ingredient is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part). The pH is adjusted to 5.0 by Acetic Acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

Example D

Soft gelatin capsules containing the following ingredients can be manufactured in a conventional manner:

Capsule contents Compound of formula (I) 5.0 mg Yellow wax 8.0 mg Hydrogenated Soya bean oil 8.0 mg Partially hydrogenated plant oils 34.0 mg Soya bean oil 110.0 mg Weight of capsule contents 165.0 mg Gelatin capsule Gelatin 75.0 mg Glycerol 85% 32.0 mg Karion 83 8.0 mg (dry matter) Titan dioxide 0.4 mg Iron oxide yellow 1.1 mg

The active ingredient is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to the usual procedures.

Example E

Sachets containing the following ingredients can be manufactured in a conventional manner:

Compound of formula (I) 50.0 mg Lactose, fine powder 1015.0 mg  Microcristalline cellulose (AVICEL PH 102) 1400.0 mg  Sodium carboxymethyl cellulose 14.0 mg Polyvinylpyrrolidon K 30 10.0 mg Magnesiumstearate 10.0 mg Flavoring additives  1.0 mg

The active ingredient is mixed with lactose, microcristalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidon in water. The granulate is mixed with magnesiumstearate and the flavouring additives and filled into sachets. 

1. A compound of formula (I)

wherein A is aryl or heteroaryl, said aryl and said heteroaryl being optionally substituted by one to three substituents independently selected from the group consisting of halogen, benzyloxy, heteroaryl-C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkoxy and halo C₁₋₆ alkoxy, or said aryl and said heteroaryl being optionally substituted by C₁₋₆ alkylenedioxy; X is —N(R¹)(R²) or —N⁺(R¹)(R²)(R⁷); i) R¹ and R² are, independently to each other, hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, hydroxy C₂₋₆ alkyl, C₁₋₆ alkoxy C₂₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆ alkyl, C₇₋₁₀ bicycloalkyl, phenyl C₁₋₃ alkyl, heteroaryl C₁₋₃ alkyl, heterocyclyl or heterocyclyl C₁₋₆ alkyl, in which the cycloalkyl of said C₃₋₇ cycloalkyl and said C₃₋₇ cycloalkyl C₁₋₆ alkyl, the phenyl of said phenyl C₁₋₃ alkyl, the heteroaryl of said heteroaryl C₁₋₃ alkyl and the heterocyclyl of said heterocyclyl and said heterocyclyl C₁₋₆ alkyl are optionally substituted by one to three substituents independently selected from the group consisting of R^(d); or R¹ and R², together with the nitrogen atom to which they are attached, form heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of R^(d), and one of the ring carbon atoms of said heterocyclyl formed by R¹ and R² being optionally replaced with a carbonyl group; and/or one of the ring carbon atoms of the heterocyclyl formed by R¹ and R² may be a ring carbon atom of another ring which is C₃₋₇ cycloalkyl or heterocyclyl, one or two ring carbon atoms of said another ring being optionally replaced by a carbonyl group, and said another ring being optionally substituted by C₁₋₆ alkyl; R³ and R⁴ are, independently to each other, hydrogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, carboxyl, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, halogen or halo C₁₋₆ alkyl; or R³ and R⁴, together with the carbon atom to which they are attached, form C₃₋₇ cycloalkyl or heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of C₁₋₄ alkyl, halo C₁₋₄ alkyl and halogen; or ii) R¹ is hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkinyl, hydroxy C₁₋₆ alkyl, C₁₋₆ alkoxy C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆ alkyl, C₇₋₁₀ bicycloalkyl, phenyl C₁₋₃ alkyl, heteroaryl C₁₋₃ alkyl, heterocyclyl or heterocyclyl C₁₋₆ alkyl, in which the cycloalkyl of said C₃₋₇ cycloalkyl and said C₃₋₇ cycloalkyl C₁₋₆ alkyl, the phenyl of said phenyl C₁₋₃ alkyl, the heteroaryl of said heteroaryl C₁₋₃ alkyl and the heterocyclyl of said heterocyclyl and said heterocyclyl C₁₋₆ alkyl are optionally substituted by one to three substituents independently selected from the group consisting of R^(d); R³ is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆ alkyl, halogen or halo C₁₋₆ alkyl; R² and R⁴, together with the nitrogen atom to which R² is attached, the carbon atom to which R⁴ is attached and the C₁₋₂ alkylene between said nitrogen atom and said carbon atom, if any, form heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of C₁₋₆ alkyl and fluorine; R⁵ and R⁶ are, independently to each other, hydrogen, fluoro, C₁₋₆ alkyl or C₃₋₇ cycloalkyl; R⁷ is C₁₋₆ alkyl; R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are, independently to each other, hydrogen, C₁₋₆ alkyl or C₃₋₇ cycloalkyl; R^(d) is hydroxy, cyano, NR^(a)R^(b), halogen, C₁₋₆ alkyl, halo C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkoxycarbonyl, acyl, —C(O)NR^(a)R^(b), —NR^(a)—C(O)—R^(b), —NR^(a)—C(O)—OR^(b), —NR^(a)—C(O)—NR^(b), —NR^(a)—SO₂—R^(b), —NR^(a)—SO₂—NR^(b)R^(c), —OC(O)NR^(a)R^(b), —OC(O)OR^(a), C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylthio, phenyl, phenyl C₁₋₃ alkyl, heteroaryl, heteroaryl C₁₋₃ alkyl and heterocyclyl, and the phenyl of said phenyl and said phenyl C₁₋₃ alkyl, the heteroaryl of said heteroaryl and said heteroaryl C₁₋₃ alkyl, and the heterocyclyl being optionally substituted by one to three substituents independently selected from the group consisting of hydroxy, cyano, NR^(a)R^(b), halogen, C₁₋₆ alkyl, halo C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, acyl, —C(O)NR^(a)R^(b), —NR^(a)—C(O)—R^(b), —NR^(a)—C(O)—OR^(b), —NR^(a)—C(O)—NR^(b), —NR^(a)SO₂—R^(b), —NR^(a)—SO₂—NR^(b)R^(c), —OC(O)NR^(a)R^(b), —OC(O)OR^(a), C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl and C₁₋₆ alkylthio, and one or two ring carbon atoms of the heterocyclyl being optionally replaced with a carbonyl group; R^(a), R^(b) and R^(c) are independently hydrogen or C₁₋₆ alkyl; n is an integer of 0 to 3; m is an integer of 0 to 3; m+n is an integer of 1 to 5; or a pharmaceutically acceptable salts thereof; wherein, unless otherwise indicated, the term “aryl” means phenyl or naphthyl; the term “heterocyclyl” means non-aromatic mono- or bi-cyclic radicals of four to nine ring atoms in which one to three ring atoms are heteroatoms independently selected from N, O and S(O)_(n) (where n is an integer from 0 to 2), the remaining ring atoms being C; the term “heteroaryl” means a monocyclic or bicyclic radical of 5 to 10 ring atoms having one to three ring heteroatoms independently selected from N, O, and S, the remaining ring atoms being C; the term “acyl” means R—C(O)—, in which R is C₁₋₆ alkyl, halo C₁₋₆ alkyl, C₃₋₇ cycloalkyl or C₃₋₇ cycloalkyl C₁₋₆ alkyl.
 2. The compounds of claim 1 wherein A is aryl, said aryl being optionally substituted by one to three substituents independently selected from the group consisting of halogen, benzyloxy, heteroaryl-C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkoxy and halo C₁₋₆ alkoxy, or said aryl being optionally substituted by C₁₋₆ alkylenedioxy.
 3. The compounds of claim 2 wherein R¹ and R² are, independently to each other, hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, hydroxy C₂₋₆ alkyl, C₁₋₆ alkoxy C₂₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆ alkyl, C₇₋₁₀ bicycloalkyl, phenyl C₁₋₃ alkyl, heteroaryl C₁₋₃ alkyl, heterocyclyl or heterocyclyl C₁₋₆ alkyl; and R³ and R⁴ are, independently to each other, hydrogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, carboxyl, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, halogen or halo C₁₋₆ alkyl; or R³ and R⁴, together with the carbon atom to which they are attached, form C₃₋₇ cycloalkyl or heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of C₁₋₄ alkyl, halo C₁₋₄ alkyl and halogen.
 4. The compounds of claim 3 wherein the cycloalkyl of said C₃₋₇ cycloalkyl and said C₃₋₇ cycloalkyl C₁₋₆ alkyl, the phenyl of said phenyl C₁₋₃ alkyl, the heteroaryl of said heteroaryl C₁₋₃ alkyl and the heterocyclyl of said heterocyclyl and said heterocyclyl C₁₋₆ alkyl are substituted by one to three substituents independently selected from the group consisting of R^(d).
 5. The compounds of claim 2 wherein R¹ and R², together with the nitrogen atom to which they are attached, form heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of R^(d), and one of the ring carbon atoms of said heterocyclyl formed by R¹ and R² being optionally replaced with a carbonyl group; and R³ and R⁴ are, independently to each other, hydrogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, carboxyl, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, halogen or halo C₁₋₆ alkyl; or R³ and R⁴, together with the carbon atom to which they are attached, form C₃₋₇ cycloalkyl or heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of C₁₋₄ alkyl, halo C₁₋₄ alkyl and halogen.
 6. The compounds of claim 5 wherein one of the ring carbon atoms of the heterocyclyl formed by R¹ and R² may be a ring carbon atom of another ring which is C₃₋₇ cycloalkyl or heterocyclyl, one or two ring carbon atoms of said another ring being optionally replaced by a carbonyl group, and said another ring being optionally substituted by C₁₋₆ alkyl.
 7. The compounds of claim 2 wherein R¹ is hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkinyl, hydroxy C₁₋₆ alkyl, C₁₋₆ alkoxy C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆ alkyl, C₇₋₁₀ bicycloalkyl, phenyl C₁₋₃ alkyl, heteroaryl C₁₋₃ alkyl, heterocyclyl or heterocyclyl C₁₋₆ alkyl.
 8. The compounds of claim 7 wherein the cycloalkyl of said C₃₋₇ cycloalkyl and said C₃₋₇ cycloalkyl C₁₋₆ alkyl, the phenyl of said phenyl C₁₋₃ alkyl, the heteroaryl of said heteroaryl C₁₋₃ alkyl and the heterocyclyl of said heterocyclyl and said heterocyclyl C₁₋₆ alkyl are optionally substituted by one to three substituents independently selected from the group consisting of R^(d).
 9. The compounds of claim 1 wherein A is heteroaryl, said heteroaryl being optionally substituted by one to three substituents independently selected from the group consisting of halogen, benzyloxy, heteroaryl-C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkoxy and halo C₁₋₆ alkoxy, or said heteroaryl being optionally substituted by C₁₋₆ alkylenedioxy.
 10. The compounds of claim 9 wherein R¹ and R² are, independently to each other, hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, hydroxy C₂₋₆ alkyl, C₁₋₆ alkoxy C₂₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆ alkyl, C₇₋₁₀ bicycloalkyl, phenyl C₁₋₃ alkyl, heteroaryl C₁₋₃ alkyl, heterocyclyl or heterocyclyl C₁₋₆ alkyl; and wherein R³ and R⁴ are, independently to each other, hydrogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, carboxyl, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, halogen or halo C₁₋₆ alkyl; or R³ and R⁴, together with the carbon atom to which they are attached, form C₃₋₇ cycloalkyl or heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of C₁₋₄ alkyl, halo C₁₋₄ alkyl and halogen.
 11. The compounds of claim 10 wherein the cycloalkyl of said C₃₋₇ cycloalkyl and said C₃₋₇ cycloalkyl C₁₋₆ alkyl, the phenyl of said phenyl C₁₋₃ alkyl, the heteroaryl of said heteroaryl C₁₋₃ alkyl and the heterocyclyl of said heterocyclyl and said heterocyclyl C₁₋₆ alkyl are substituted by one to three substituents independently selected from the group consisting of R^(d).
 12. The compounds of claim 9 wherein R¹ and R², together with the nitrogen atom to which they are attached, form heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of R^(d), and one of the ring carbon atoms of said heterocyclyl formed by R¹ and R² being optionally replaced with a carbonyl group; and R³ and R⁴ are, independently to each other, hydrogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, carboxyl, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, halogen or halo C₁₋₆ alkyl; or R³ and R⁴, together with the carbon atom to which they are attached, form C₃₋₇ cycloalkyl or heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of C₁₋₄ alkyl, halo C₁₋₄ alkyl and halogen.
 13. The compounds of claim 12 wherein one of the ring carbon atoms of the heterocyclyl formed by R¹ and R² may be a ring carbon atom of another ring which is C₃₋₇ cycloalkyl or heterocyclyl, one or two ring carbon atoms of said another ring being optionally replaced by a carbonyl group, and said another ring being optionally substituted by C₁₋₆ alkyl.
 14. The compounds of claim 9 wherein R¹ is hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkinyl, hydroxy C₁₋₆ alkyl, C₁₋₆ alkoxy C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆ alkyl, C₇₋₁₀ bicycloalkyl, phenyl C₁₋₃ alkyl, heteroaryl C₁₋₃ alkyl, heterocyclyl or heterocyclyl C₁₋₆ alkyl.
 15. The compounds of claim 14 wherein the cycloalkyl of said C₃₋₇ cycloalkyl and said C₃₋₇ cycloalkyl C₁₋₆ alkyl, the phenyl of said phenyl C₁₋₃ alkyl, the heteroaryl of said heteroaryl C₁₋₃ alkyl and the heterocyclyl of said heterocyclyl and said heterocyclyl C₁₋₆ alkyl are optionally substituted by one to three substituents independently selected from the group consisting of R^(d).
 16. The compounds of claim 1, wherein R³ and R⁴ are, independently to each other, hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆ alkyl, halogen or halo C₁₋₆ alkyl; R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are hydrogen; R^(d) is hydroxy, cyano, NR^(a)R^(b), halogen, C₁₋₆ alkyl, halo C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, acyl, —C(O)NR^(a)R^(b), —NR^(a)—C(O)—R^(b), —NR^(a)—C(O)—OR^(b), —NR^(a)—C(O)—NR^(b), —NR^(a)—SO₂—R^(b), —NR^(a)SO₂—NR^(b)R^(c), —OC(O)NR^(a)R^(b), —OC(O)OR^(a), C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylthio, phenyl, phenyl C₁₋₃ alkyl, heteroaryl, heteroaryl C₁₋₃ alkyl and heterocyclyl, and the phenyl of said phenyl and said phenyl C₁₋₃ alkyl, the heteroaryl of said heteroaryl and said heteroaryl C₁₋₃ alkyl, and the heterocyclyl being optionally substituted by one to three substituents independently selected from the group consisting of hydroxy, cyano, NR^(a)R^(b), halogen, C₁₋₆ alkyl, halo C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, acyl, —C(O)NR^(a)R^(b), —NR^(a)—C(O)—R^(b), —NR^(a)—C(O)—OR^(b), —NR^(a)—C(O)—NR^(b), —NR^(a)—SO₂—R^(b), —NR^(a)—SO₂—NR^(b)R^(c), —OC(O)NR^(a)R^(b), —OC(O)OR^(a), C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl and C₁₋₆ alkylthio, and one or two ring carbon atoms of the heterocyclyl being optionally replaced with a carbonyl group.
 17. The compounds of claim 1, wherein A is phenyl optionally substituted by one to three substituents independently selected from the group consisting of halogen, benzyloxy, heteroaryl-C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkoxy and halo C₁₋₆ alkoxy, or A is phenyl optionally substituted by C₁₋₆ alkylenedioxy.
 18. The compounds of claim 1, wherein A is phenyl substituted by one or two halogen atoms independently selected from the group consisting of chlorine and fluorine.
 19. The compounds of claim 1, wherein A is phenyl substituted by two halogen atoms independently selected from the group consisting of chlorine and fluorine at its 3,4 or 3,5 position.
 20. The compounds of claim 1, wherein X is —N(R¹)(R²).
 21. The compounds of claim 20, wherein at least one of R¹ and R² is other than hydrogen.
 22. The compounds of claim 20, wherein R¹ is hydrogen, C₁₋₆ alkyl, or hydroxy C₂₋₆ alkyl and R² is C₃₋₇ cycloalkyl, heterocyclyl, heterocyclyl C₁₋₆ alkyl, C₇₋₁₀ bicycloalkyl, hydroxy C₂₋₆ alkyl or C₁₋₆ alkoxy C₂₋₆ alkyl, in which the cycloalkyl and the heterocyclyl of said heterocyclyl and said heterocyclyl C₁₋₆ alkyl are optionally substituted by one or two substituents independently selected from the group consisting of C₁₋₆ alkyl, hydroxy, heteroaryl and C₁₋₆ alkoxy.
 23. The compounds of claim 20, wherein R¹ is hydrogen and R² is heterocyclyl.
 24. The compounds of claim 20, wherein m+n is an integer of 1 or
 2. 25. The compounds of claim 20, wherein R³, R⁴, R⁵ and R⁶ are hydrogen.
 26. The compounds of claim 20, wherein R¹ and R², together with the nitrogen atom to which they are attached, form heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of R^(d), and one of the ring carbon atoms of said heterocyclyl formed by R¹ and R² being optionally replaced with a carbonyl group; and/or one of the ring carbon atoms of the heterocyclyl formed by R¹ and R² may be a ring carbon atom of another ring which is C₃₋₇ cycloalkyl or heterocyclyl, one or two ring carbon atoms of said another ring being optionally replaced by a carbonyl group, and said another ring being optionally substituted by C₁₋₆ alkyl.
 27. The compounds of claim 26, wherein the heterocyclyl formed by R¹ and R², together with the nitrogen atom to which they are attached, is a mono-cyclic radical of five or six ring atoms in which one more ring atom, in addition to the nitrogen atom, may be a heteroatom independently selected from N, O and S(O)_(n) (where n is an integer from 0 to 2).
 28. The compounds of claim 26, wherein the heterocyclyl formed by R¹ and R², together with the nitrogen atom to which they are attached, is piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl or 1,1-dioxo-hiomorphlinyl.
 29. The compounds of claim 26, wherein the heterocyclyl formed by R¹ and R², together with the nitrogen atom to which they are attached, is piperidyl or pyrrolidinyl.
 30. The compounds of claim 26, wherein the heterocyclyl formed by R¹ and R², together with the nitrogen atom to which they are attached, is optionally substituted by one or two substituents independently selected from the group consisting of hydroxy, phenyl and hydroxy C₁₋₆ alkyl, and/or one of the ring carbon atoms of the heterocyclyl formed by R¹ and R² may be shared by another ring which is five or six membered mono-cyclic heterocyclyl, one or two ring carbon atoms of said another ring being optionally replaced by a carbonyl group.
 31. The compounds of claim 26, wherein m+n is an integer of 1 to
 3. 32. The compounds of claim 26, wherein R³, R⁴, R⁵ and R⁶ are hydrogen.
 33. The compounds of claim 1, which is 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(4-piperidin-1-yl-butyl)-[1,4]diazepan-5-one, 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one, 1-[(E)-3-(4-Chloro-3-fluoro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one, 8-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione, 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[3-(4-hydroxy-4-phenyl-piperidin-1yl)-propyl]-[1,4]diazepan-5-one, (+/−)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[3-(3-hydroxy-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one, 8-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one, 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[3-(tetrahydro-pyran-4-ylamino)-ethyl]-[1,4]diazepan-5-one, (S)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[3-(2-hydroxymethyl-pyrrolidin-1-yl)-ethyl]-[1,4]diazepan-5-one, or 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(2-pyrrolidin-1-yl-ethyl)-[1,4]diazepan-5-one.
 34. The compounds of claim 1, which is 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[3-((−, cis)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one, 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[3-(3-hydroxy-4,4-dimethyl-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one, (cis)-1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[3-(3-hydroxy-5-methyl-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one, 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[2-hydroxy-3-(3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one, 1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[(S)-2-hydroxy-3-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one, 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[(S)-2-hydroxy-3-(3-hydroxy-4,4-dimethyl -piperidin-1-yl)-propyl]-[1,4]diazepan-5-one, 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[(S)-2-hydroxy-3-(cis-3-hydroxy-5-methyl-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one, 1-[(E)-3-(4-Chloro-3-fluoro-phenyl)-acryloyl]-4-[4-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-[1,4]diazepan-5-one, (cis)-1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[4-(3-hydroxy-5-methyl-piperidin-1-yl)-butyl]-[1,4]diazepan-5-one, 1-[(E)-3-(3-Chloro-phenyl)-acryloyl]-4-[3-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one, or 1-[(E)-3-(5,6-Dichloro-pyridin-3-yl)-acryloyl]-4-[3-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one.
 35. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient. 